JP2023502476A - Pyridopyrimidinone Derivatives as AHR Antagonists - Google Patents

Abstract

The present disclosure provides compounds of formula (Ia) and pharmaceutically acceptable salts thereof, pharmaceutical compositions containing them, methods of preparing them, intermediate compounds useful in preparing them, and diseases, particularly cancer or modulation thereof. It relates to methods of treatment or prevention of conditions with compromised immune responses or other disorders associated with aberrant AHR signaling. These compounds may also be useful for treating cancer when administered in combination with at least one additional therapy. JPEG2023502476000348.jpg44167

Description

No. 62/939,377, filed November 22, 2019; U.S. Patent Application No. 63/050,416, filed July 10, 2020; No. 63/091,192, filed October 13, 2020, is claimed and is hereby incorporated by reference in its entirety.

novel 3,6,8-trisubstituted pyrido[3,4-d]pyrimidin-4(3H)-one compounds of formula (Ia) and pharmaceutically acceptable salts thereof, methods of preparing said compounds and salts, said Intermediate compounds useful for preparing the compounds and salts, pharmaceutical compositions comprising said compounds and salts, and the treatment of diseases, particularly cancer or conditions with a dysregulated immune response or other disorders associated with aberrant AHR signaling Alternatively, methods of using the compounds and salts for prophylaxis are disclosed herein. Compositions comprising at least one such compound and/or pharmaceutically acceptable salt thereof and at least one additional therapy and at least one such compound and/or pharmaceutically acceptable salt thereof and at least Also disclosed herein are methods of treating cancer comprising administering one additional therapy.

Aromatic hydrocarbon receptors (AHRs) are ligand-activated transcription factors belonging to the basic helix-loop-helix/Per-Arnt-Sim (bHLH/PAS) family located in the cytosol. Upon ligand binding, AHR translocates to the nucleus where it heterodimerizes with ARNT (AHR nuclear transporter) and simultaneously interacts with DRE (dioxin response element) of AHR-responsive genes to regulate their transcription. do. AHR is best known to bind environmental toxins and induce metabolic machinery such as the cytochrome P450 enzymes (e.g., CYP1A1, CYP1A2, and CYP1B1) required for their removal (Reyes et al., Science). , 1992, 256 (5060): 1 193-5). Activation of AHR by xenobiotics has demonstrated its role in many cellular processes such as embryogenesis, tumorigenesis, and inflammation.

AHR is expressed in many cells of the immune system, including dendritic cells (DC), macrophages, T cells, and NK cells, and plays an important role in immune regulation (Nguyen et al., Front. Immunol. , 2014, 5:551). The classical exogenous AHR ligands TCDD and 3-methylcholanthrene, for example, are known to induce profound immunosuppression, promote carcinogenesis, and induce tumor growth (Gramatzki et al., Oncogene Bui et al., Oncogene, 2009, 28(41):3642-51; Esser et al., Trends Immunol., 2009, 30:447-454). In immunosuppressive settings, AHR activation promotes regulatory T cell generation, directly and indirectly inhibits Th1 and Th17 differentiation, and reduces DC activation and maturation (Wang et al., Clin Exp. Immunol., 2014, 177(2): 521-30; Mezrich et al., J. Immunol., 2010, 185(6): 3190-8; 94(5):528-35; Nguyen et al., PNAS, 2010, 107(46):19961-6). AHR activation regulates the innate immune response, and constitutive AHR expression was shown to negatively regulate the type 1 interferon response to viral infection (Yamada et al., Nat. Immunol., 2016, 17 (6):687-94). Moreover, mice with naturally constitutively active AHR develop tumors (Andersson et al., PNAS, 2002, 99(15):9990-5).

In addition to xenobiotics, AHR can also bind metabolites of tryptophan degradation. Tryptophan metabolites such as kynurenine and kynurenic acid are endogenous AHR ligands that activate AHR under physiological conditions (DiNatale et al., Toxicol. Sci., 2010, 115(1):89-97; Mezrich et al., J. Immunol., 2010, 185(6):3190-8; Opitz et al., Nature, 2011, 478(7368):197-203). Other endogenous ligands are known to bind AHR, although their physiological roles are currently unknown (Nguyen & Bradfield, Chem. Res. Toxicol., 2008, 21(1):102-116).

The immunosuppressive properties of kynurenine and tryptophan degradation are well documented and implicated in cancer-associated immunosuppression. The enzymes indoleamine-2,3-dioxygenase 1 and 2 (IDO1/IDO2) and tryptophan-2,3-dioxygenase 2 (TDO2) are responsible for catalyzing the first rate-limiting step of tryptophan metabolism. there is IDO1/2-mediated degradation of tryptophan in tumors and tumor-draining lymph nodes reduces antitumor immune responses, and inhibition of IDO can suppress tumorigenesis in animal models (Uyttenhove et al., Nat. Med., 2003). Liu et al., Blood, 2005, 115(17):3520-30; Muller et al., Nat. Med., 11(3):312-9; Metz, Cancer Res., 2007, 67(15):7082-7).

TDO2 is also strongly expressed in cancer and can lead to the production of immunosuppressive kynurenines. In gliomas, activation of AHR by kynurenines downstream of TDO-mediated tryptophan degradation increases tumor growth as a result of inhibition of anti-tumor immune responses and direct promotion of tumor cell survival and motility (Opitz et al. ., Nature, 2011, 478(7368):197-203). Thus, AHR ligands produced by tumor cells act in both autocrine and paracrine ways on tumor cells and lymphocytes, respectively, to promote tumor growth.

Additional therapies may be useful in treating cancer in combination with AhR. Immune checkpoint inhibitors (ICIs) have been used in cancer therapy to augment the host's immune response. Non-limiting examples of ICI targets include programmed death 1 (PD-1), ligand of PD-1 (PD-L1), and cytotoxic T lymphocyte antigen 4 (CTLA-4).

PD-1 is highly expressed by activated T cells, B cells, dendritic cells (DC), and natural killer cells (NK), whereas PD-L1 is expressed on several types of tumor cells. obtain.
ICI includes melanoma, non-small cell lung cancer, renal cell carcinoma, head and neck squamous cell carcinoma, Hodgkin's lymphoma, urothelial carcinoma, small cell lung cancer, esophageal squamous cell carcinoma, cervical cancer, primary mediastinal large B-cell lymphoma , MSI-H/dMMR colon cancer, hepatocellular carcinoma, Merkel cell carcinoma, triple-negative breast cancer, and cutaneous squamous cell carcinoma.

Reyes et al. , Science, 1992, 256(5060): 1 193-5 Nguyen et al. , Front. Immunol. , 2014, 5:551 Gramatzki et al. , Oncogene, 2009, 28(28):2593-605 Bui et al. , Oncogene, 2009, 28(41):3642-51 Esser et al. , Trends Immunol. , 2009, 30:447-454 Wang et al. , Clin. Exp. Immunol. , 2014, 177(2):521-30 Mezrich et al. , J. Immunol. , 2010, 185(6):3190-8 Wei et al. , Lab. Invest. , 2014, 94(5):528-35 Nguyen et al. , PNAS, 2010, 107(46): 19961-6 Yamada et al. , Nat. Immunol. , 2016, 17(6):687-94 Andersson et al. , PNAS, 2002, 99(15):9990-5 Di Natale et al. , Toxicol. Sci. , 2010, 115(1):89-97 Mezrich et al. , J. Immunol. , 2010, 185(6):3190-8 Opitz et al. , Nature, 2011, 478(7368): 197-203 Nguyen & Bradfield, Chem. Res. Toxicol. , 2008, 21(1):102-116

The present disclosure relates to novel 3,6,8-trisubstituted pyrido[3,4-d]pyrimidin-4(3H)-ones of formula (I) or formula (Ia) and/or pharmaceutically acceptable salts thereof . The compounds of the present disclosure have surprisingly been found to effectively inhibit AHR, thus exogenous and endogenous AHR ligands are responsible for dysregulated immune responses, uncontrolled cell growth, tumor cell proliferation and/or survival of cancer cells, immunosuppression in the setting of cancer, an inappropriate cellular immune response, or an inappropriate cellular inflammatory response, or uncontrolled cell growth, tumor cells diseases with immune suppression in the setting of cancer, an inappropriate cellular immune response, or an inappropriate cellular inflammatory response, in particular uncontrolled cell growth, proliferation and/or survival of tumor cells , diseases in which immunosuppression in the context of cancer, inappropriate cellular immune responses, or inappropriate cellular inflammatory responses are mediated by AHR, such as liquid and solid tumors, and/or metastases thereof, such as brain tumors and brain Head and neck tumors, including metastases, thoracic tumors, including non-small cell and small cell lung tumors, gastrointestinal tumors, including colon, colorectal, and pancreatic tumors, liver tumors, endocrine tumors, breast and other gynecologic tumors, kidney, It can be used to treat or prevent urological tumors, including bladder and prostate tumors, skin tumors, and sarcoma, and/or metastases thereof, and the like.

The present disclosure also relates to pharmaceutical compositions comprising at least one entity selected from compounds of formula (I) or formula (Ia) and pharmaceutically acceptable salts thereof. The present disclosure also relates to methods of treatment comprising administering at least one compound, pharmaceutically acceptable salt thereof, and/or pharmaceutical composition of the present disclosure. In some embodiments, the present disclosure provides methods of treating diseases or conditions mediated by AHR signaling. In some embodiments, the present disclosure provides methods of treating diseases or conditions associated with aberrant AHR signaling. In some embodiments, the present disclosure provides methods of inhibiting cancer cell proliferation mediated by AHR signaling.

Dosing regimen for an in vivo syngeneic model study using CT26 Balb/C mice. Tumor growth curves of vehicle versus single agent PD-L1 antibody or PD-L1 antibody together with Compound #7 in a syngeneic colon cancer mouse model refractory to anti-PD-L1 therapy. Tumor weight at the end of testing of vehicle versus single agent PD-L1 antibody or PD-L1 antibody together with Compound #7 in a syngeneic colon cancer mouse model refractory to anti-PD-L1 therapy. Tumor growth curves of vehicle versus single agent PD-L1 antibody or PD-L1 antibody together with Compound #30 in a syngeneic colon cancer mouse model refractory to anti-PD-L1 therapy. Tumor weights at the end of testing of vehicle versus single agent PD-L1 antibody or PD-L1 antibody together with Compound #30 in a syngeneic colon cancer mouse model refractory to anti-PD-L1 therapy. Tumor growth curves of vehicle versus single agent PD-L1 antibody or PD-L1 antibody together with Compound #30 in a syngeneic colon cancer mouse model refractory to anti-PD-L1 therapy. Tumor weights at the end of testing of vehicle versus single agent PD-L1 antibody or PD-L1 antibody together with Compound #30 in a syngeneic colon cancer mouse model refractory to anti-PD-L1 therapy. Tumor growth curves of vehicle versus single agent PD-L1 antibody or PD-L1 antibody together with Compound #9 in a syngeneic colon cancer mouse model refractory to anti-PD-L1 therapy. Tumor weight at the end of testing of vehicle versus single agent PD-L1 antibody or PD-L1 antibody together with Compound #9 in a syngeneic colon cancer mouse model refractory to anti-PD-L1 therapy. Tumor growth curves of vehicle versus single agent PD-L1 antibody or PD-L1 antibody together with Compound #9 in a syngeneic colon cancer mouse model refractory to anti-PD-L1 therapy. Tumor weight at the end of testing of vehicle versus single agent PD-L1 antibody or PD-L1 antibody together with Compound #9 in a syngeneic colon cancer mouse model refractory to anti-PD-L1 therapy. Tumor growth curves of vehicle versus single agent PD-L1 antibody or PD-L1 antibody together with Compound #46 in a syngeneic colon cancer mouse model refractory to anti-PD-L1 therapy. Tumor weights at the end of testing of vehicle versus single agent PD-L1 antibody or PD-L1 antibody together with Compound #46 in a syngeneic colon cancer mouse model refractory to anti-PD-L1 therapy. FIG. 4 shows a plot of mean plasma concentrations of compound #46 over time after 1 mg/kg IV and 10 mg/kg PO in CD1 mice. FIG. 4 shows a plot of mean plasma concentrations of Compound #46 over time after 1 mg/kg IV and 3 mg/kg PO in SD rats. 9 shows a plot of mean plasma concentrations of compound #9 over time after 1 mg/kg IV and 10 mg/kg PO in CD1 mice. 9 shows a plot of mean plasma concentrations of Compound #9 over time after 1 mg/kg IV and 3 mg/kg PO in SD rats.

As used herein, the term "pharmaceutically acceptable salt" refers to a salt that is pharmaceutically acceptable as defined herein and that possesses the desired pharmacological activity of the parent compound. Non-limiting examples of pharmaceutically acceptable salts are derived from inorganic acids, of which hydrochloric, hydrobromic, hydroiodic, sulfuric, nitric, and phosphoric acids are non-limiting examples. and non-limiting examples acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, stearic acid, malic acid, maleic acid, malonic acid, salicylic acid, succinic acid, fumaric acid, tartaric acid, citric acid , benzoic acid, cinnamic acid, mandelic acid, p-toluenesulfonic acid, methanesulfonic acid, ethanesulfonic acid, and lactic acid are derived from certain organic acids.

Additional non-limiting examples of pharmaceutically acceptable salts are when an acidic proton in the parent compound is replaced by a metal ion, non-limiting examples of which are alkali metal ions and alkaline earth metal ions. Some are formed and some are formed when acidic protons present in the parent compound are replaced by ammonium ions, primary ammonium ions, secondary ammonium ions, tertiary ammonium ions, or quaternary ammonium ions. Non-limiting examples of alkali metals and alkaline earth metals include sodium, potassium, lithium, calcium, aluminum, magnesium, copper, zinc, iron, and manganese. Additional non-limiting examples of pharmaceutically acceptable salts are those containing one or more counterions and zwitterions.

Ranges provided herein are understood to be shorthand for all of the values within the range. For example, the range from 1 to 50 is 1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21 , 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46 , 47, 48, 49, or 50, any number, combination of numbers, or subranges thereof. The same convention applies to any other ranges described herein, even if the values within the range are not specifically called out herein.

As used herein, the terms "checkpoint inhibitor" and "checkpoint inhibitor therapy" inhibit one or more inhibitory pathways, thereby allowing greater immune activity. Used interchangeably to refer to any therapeutic agent, including any small molecule chemical compound, antibody, nucleic acid molecule, or polypeptide, or any fragment thereof. In some embodiments, checkpoint inhibitor therapy comprises administering at least one checkpoint inhibitor to a patient in need of such treatment.

The term "compound" as used herein, unless otherwise specified, refers to a group of stereoisomers (e.g. a group of racemates, a group of cis/trans stereoisomers, or a group of (E) and (Z) Refers to a group of molecules that have the same chemical structure as stereoisomers. Therefore, geometric and conformational mixtures of the present compounds and salts are within the scope of this disclosure. Unless otherwise specified, all tautomeric forms of the compounds of the disclosure are within the scope of the disclosure.

As used herein, "stereoisomer" refers to enantiomers and diastereomers.

As used herein, the term "tautomer" refers to one of two or more isomers of a compound that exist together in equilibrium and are readily interconverted by movement of atoms or groups within the molecule. .

Unless otherwise indicated, the nomenclature used to describe chemical groups or moieties used herein reads the name from left to right, with the point of attachment to the rest of the molecule on the right side of the name. follow the custom. For example, the group “(C _1-3 alkoxy)C _1-3 alkyl” attaches to the remainder of the molecule at the alkyl terminus. Further examples are methoxyethyl where the point of attachment is on the ethyl end and methylamino where the point of attachment is on the amine end.

）が結合点を表現する。 Unless otherwise indicated, when a chemical group is described by its formula or structure with a terminal attachment indicated by a "-", it will be understood that the "-" represents the point of attachment. In some embodiments, a wavy line (i.e.

) represents the attachment point.

As used herein, an "acyl" or "alkanoyl" is a functional group having the formula RCO-, where R is attached through a single bond to the carbon atom of the carbonyl functionality and "-" indicates the point of attachment to the rest of the molecule. Non-limiting examples of acyl include formyl (HC(O)--, also called methanoyl), acetyl (CH ₃ C(O)--, also called ethanoyl), and benzoyl (PhC(O)--).

As used herein, the term “alkyl” or “aliphatic” refers to a linear (i.e., unbranched) or branched, substituted or unbranched, fully saturated, single point of attachment to the rest of the molecule. A substituted hydrocarbon chain is meant. Unless otherwise specified, alkyl groups are hydrocarbon chains of 1-20 alkyl carbon atoms. In some embodiments, the alkyl group contains 1-12 carbon atoms (C ₁ -C ₁₂ ). In some embodiments, the alkyl group contains 1-8 carbon atoms (C ₁ -C ₈ ). In some embodiments, the alkyl group contains 1-6 carbon atoms (C ₁ -C ₆ ). In some embodiments, the alkyl group contains 1-4 carbon atoms (C ₁ -C ₄ ). In some embodiments, cyclic alkyl groups contain 3-6 carbon atoms (C ₃ -C ₆ ). Non-limiting examples of substituted and unsubstituted straight chain, branched chain, and cyclic alkyl groups include methyl, ethyl, n-propyl, iso-propyl, cyclopropyl, n-butyl, sec-butyl, iso- butyl, tert-butyl, cyclobutyl, cyclopentyl, cyclohexyl, hydroxymethyl, chloromethyl, fluoromethyl, trifluoromethyl, aminomethyl, 2-aminoethyl, 3-aminopropyl, 4-aminobutyl, dimethylaminomethyl, 2-dimethyl There are aminoethyl, 3-dimethylaminopropyl, 4-dimethylaminobutyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, trifluoroethyl and trifluoropropyl.

As used herein, "alkoxy" refers to an alkyl group as defined above attached to a main carbon chain through an oxygen ("alkoxy") atom.

As used herein, "halo" and "halogen" are interchangeable and refer to halogen atoms such as fluoro (F), chloro (Cl), bromo (Br), and iodo (I).

"Haloalkyl" refers to an alkyl group substituted with one or more halo atoms (F, Cl, Br, I). For example, "fluoromethyl" refers to a methyl group substituted with one or more fluoro atoms (eg, monofluoromethyl, difluoromethyl, or trifluoromethyl).

"Haloalkoxy" refers to alkoxy groups substituted with one or more halo atoms (F, Cl, Br, I). For example, "fluoromethoxy" refers to a methoxy group substituted with one or more fluoro atoms (eg, monofluoromethoxy, difluoromethoxy, or trifluoromethoxy).

"Hydroxyalkyl" refers to an alkyl group substituted with one or more hydroxy groups (-OH).

The terms "cycloalkyl" and "cycloalkyl group", used interchangeably herein, refer to a saturated monovalent carbon cyclic group of 3 to 12 carbon atoms with a single point of attachment to the rest of the molecule. A hydrogen group. A cycloalkyl group can be unsubstituted or substituted. In some embodiments, the cycloalkyl group contains 3-8 carbon atoms (C ₃ -C ₈ ). In some embodiments, the cycloalkyl group contains 3-6 carbon atoms (C ₃ -C ₆ ). Non-limiting examples of substituted and unsubstituted cycloalkyls include cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclobutylmethyl, cyclopentyl, cyclopentylmethyl, cyclohexyl, cycloheptyl, and cyclooctyl.

The terms “alkylene” and “alkylene group”, used interchangeably herein, refer to a saturated divalent containing 1 to 12 carbon atoms (C ₁ -C ₁₂ ) (ie, two carbon atoms to the remainder of the molecule). refers to a hydrocarbon group with a point of attachment). Alkylene groups can be straight, branched, or cyclic. An alkylene group can be unsubstituted or substituted. In some embodiments, the alkylene group contains 1-8 carbon atoms (C ₁ -C ₈ ). In some embodiments, alkylene groups contain 1 to 6 carbon atoms (C ₁ -C ₆ ). In some embodiments, alkylene groups contain 1 to 4 carbon atoms (C ₁ -C ₄ ). Non-limiting examples of alkylene groups include methylene and ethylene.

The terms “alkenyl” and “alkenyl group”, used interchangeably herein, contain from 2 to 8 carbon atoms (C ₂ -C ₈ ) and have at least one site of unsaturation (ie, sp2 carbon-carbon dihydrogen). refers to a monovalent (ie, having one point of attachment to the rest of the molecule) hydrocarbon group with a double bond). Alkenyl groups may be straight chain, branched chain or cyclic. An alkenyl group can be unsubstituted or substituted. In some embodiments, the alkenyl group contains 2-6 carbon atoms (C ₂ -C ₆ ). In some embodiments, the alkenyl group contains 2-4 carbon atoms (C ₂ -C ₄ ). Alkenyl groups can have both the E and Z configurations. Non-limiting examples of alkenyl groups include ethenyl (also called vinyl), 1-propenyl, iso-propenyl, and 2-chloroethenyl.

The terms “alkenylene” and “alkenylene group”, used interchangeably herein, refer to 2 to 8 carbon atoms (C ₂ - _C8 ) refers to a divalent (ie, having two points of attachment to the rest of the molecule) hydrocarbon group. Alkenylene groups can be straight chain, branched chain, or cyclic. An alkenylene group can be unsubstituted or substituted. In some embodiments, alkylene groups contain 2 to 6 carbon atoms (C ₂ -C ₆ ). In some embodiments, the alkylene group contains 2-4 carbon atoms (C ₂ -C ₄ ). Alkylene groups can have both the E and Z configurations. A non-limiting example of an alkenyl group is ethenylene (also called vinylene).

The terms “alkynyl” and “alkynyl group”, used interchangeably herein, have from 2 to 8 carbon atoms (C ₂ to _C8 ) refers to a monovalent (ie, having one point of attachment to the rest of the molecule) hydrocarbon group. Alkynyl groups may be straight or branched. An alkynyl group can be unsubstituted or substituted. In some embodiments, the alkynyl group contains 2-6 carbon atoms (C ₂ -C ₆ ). In some embodiments, the alkynyl group contains 2-4 carbon atoms (C ₂ -C ₄ ). A non-limiting example of an alkynyl group is ethynyl.

The terms “alkynylene” and “alkynylene group”, used interchangeably herein, refer to 2 to 8 carbon atoms (C ₂ to C ₈ ) refers to a divalent (ie, having two points of attachment to the rest of the molecule) hydrocarbon group. Alkynylene groups may be straight or branched. An alkynylene group can be unsubstituted or substituted. In some embodiments, the alkynylene group contains 2-6 carbon atoms (C ₂ -C ₆ ). In some embodiments, the alkynylene group contains 2-4 carbon atoms (C ₂ -C ₄ ). A non-limiting example of an alkynylene group is ethynylene.

As used herein, an "aromatic group" or "aromatic ring" refers to a conjugated planar ring system with delocalized pi-electron orbitals composed of [4n+2] p-orbital electrons. refers to a containing chemical group, where n is an integer from 0-6. Non-limiting examples of aromatic groups include aryl and heteroaryl groups.

The terms “aryl” and “aryl group”, used interchangeably herein, are monovalent (ie, have one point of attachment to the rest of the molecule) of 6 to 20 carbon atoms (C ₆ -C ₂₀ ). (having) refers to an aromatic hydrocarbon group. An aryl group can be unsubstituted or substituted. Non-limiting examples of unsubstituted and substituted aryl groups include phenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 2- chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2,6-dichlorophenyl, 3,4-difluorophenyl, 2-hydroxyphenyl, 3-hydroxyphenyl, 4-hydroxyphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4- methoxyphenyl, 2-phenoxyphenyl, 3-phenoxyphenyl, 4-phenoxyphenyl, 2-cyanophenyl, 3-cyanophenyl, 4-cyanophenyl, 2-dimethylaminophenyl, 3-dimethylaminophenyl, 4-dimethylaminophenyl , 3-methylsulfonylphenyl, 4-methylsulfonylphenyl, 3-aminophenyl, 3-methylaminophenyl, 3-(2-hydroxyethoxy)phenyl, 2-trifluoromethylphenyl, 3-trifluoromethylphenyl, 4- There are trifluoromethylphenyl, 2-isopropylphenyl, 3-isopropylphenyl, 4-isopropylphenyl, 1-naphthyl, and 2-naphthyl.

As used herein, the term "heteroalkyl" refers to an alkyl group in which at least one carbon atom in the chain has been replaced with a heteroatom such as nitrogen, oxygen, phosphorus, and sulfur. A heteroalkyl group can be unsubstituted or substituted.

The terms “heterocycloalkyl,” “heterocycle,” “heterocyclyl,” and “heterocyclic group,” used interchangeably herein, mean that at least one of the ring atoms is nitrogen, oxygen, phosphorus, sulfur, and the like. refers to a saturated or partially unsaturated ring system of 3 to 20 atoms, which is a heteroatom of . A heterocycloalkyl group can be unsubstituted or substituted. In some embodiments, the heterocycloalkyl group contains 3-10 atoms. In some embodiments, the heterocycloalkyl group contains 3-7 atoms. In some embodiments, a heterocycloalkyl group is monocyclic. In some embodiments, a heterocycloalkyl group is bicyclic. In some embodiments, heterocycloalkyl groups contain fused rings. Non-limiting examples of unsubstituted and substituted heterocycloalkyl groups include pyrrolidinyl, N-methylpyrrolidinyl, azetidinyl, dihydrofuranyl, tetrahydrofuranyl, tetrahydropyranyl, 3-hydroxypyrrolidinyl, 3-methoxy. pyrrolidinyl, and benzodioxolyl.

がある。 The terms "heteroaryl" and "heteroaryl group", used interchangeably herein, refer to 3 to 20 heteroatoms in which at least one of the ring atoms is a heteroatom such as nitrogen, oxygen, phosphorus and sulfur Refers to the aromatic ring system of the atom. A heteroaryl group can be unsubstituted or substituted. In some embodiments, the heteroaryl group contains 5-20 atoms. In some embodiments, the heteroaryl group contains 5-9 atoms. In some embodiments, the heteroaryl group contains 5 atoms. In some embodiments, the heteroaryl group contains 6 atoms. In some embodiments, the heteroaryl group contains 7 atoms. In some embodiments, heteroaryl groups are monocyclic. In some embodiments, heteroaryl groups are bicyclic. In some embodiments, heteroaryl groups contain fused rings. Non-limiting examples of heteroaryl groups include pyridinyl, imidazolyl, imidazopyridinyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, 2-thienyl, 3-thienyl, isoxazolyl, thiazolyl, oxadiazolyl, 3-methyl -1,2,4-oxadiazolyl, 3-phenyl-1,2,4-oxadiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, tetrahydroisoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl , triazinyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, furopyridinyl, and 1H-pyrrolo[2,3-b]pyridinyl. Non-limiting examples of heteroaryl groups include:

There is

As used herein, the phrase "optionally substituted" means "substituted" or unsubstituted. As used herein, the term "substituted" refers to a group (alkyl, alkylene, alkenyl, alkenylene, alkynyl, alkynylene, aryl, heterocycloalkyl, or heteroaryl) on a group. refers to the replacement of one or more hydrogen atoms by one or more substituents. Non-limiting examples of substituents that replace one hydrogen atom include halogen, hydroxyl, and amino. Non-limiting examples of substituents that replace two hydrogen atoms include oxo and methene. A non-limiting example of a substituent that replaces three hydrogen atoms is nitrile.

Additional non-limiting examples of substituents include C ₁ -C ₆ linear, branched and cyclic alkyl groups, non-limiting examples of which include methyl, ethyl, n-propyl, iso-propyl, cyclopropyl, n-butyl sec-butyl, iso-butyl, tert-butyl, cyclobutyl, cyclopentyl, and cyclohexyl;
C ₂ -C ₈ straight chain, branched chain, and cyclic alkenyl groups, non-limiting examples of which include ethenyl (also called vinyl), 1-propenyl, and iso-propenyl;
C ₂ -C ₈ straight and branched chain alkynyl groups, non-limiting examples of which include ethynyl;
substituted and unsubstituted aryl groups, non-limiting examples of which include phenyl, 2-fluorophenyl, 3-methylphenyl, 4-chlorophenyl, 2,6-dichlorophenyl, 3,4-difluorophenyl, 3-hydroxyphenyl, 4-cyanophenyl, 2-dimethylaminophenyl, 3-methylsulfonylphenyl, 4-trifluoromethylphenyl, 3-isopropylphenyl, 1-naphthyl, and 2-naphthyl;
substituted and unsubstituted heterocyclic groups, non-limiting examples of which include pyrrolidinyl, N-methylpyrrolidinyl, azetidinyl, dihydrofuranyl, tetrahydrofuranyl, tetrahydropyranyl, 3-hydroxypyrrolidinyl, and 3-methoxy; is pyrrolidinyl;
substituted and unsubstituted heteroaryl groups, non-limiting examples of which include pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, furyl, 2-thienyl, 3-thienyl, isoxazolyl, thiazolyl, oxadiazolyl, 3-methyl-1,2,4 -oxadiazolyl, 3-phenyl-1,2,4-oxadiazolyl, indolyl, benzothiazolyl, and 1H-pyrrolo[2,3-b]pyridinyl;
—(CR _a R _b ) _z OR _c , non-limiting examples of which include —OH, —OCH ₃ , —OCH ₂ OH, and —OCH ₂ CH ₃ ;
—(CR _a R _b )zN(R _c )(R _d ), non-limiting examples of which include —NH ₂ , —NHCH ₃ , —N(CH ₃ ) ₂ , —CH ₂ NH ₂ , —CH there are ₂ NHCH ₃ ,
Halogen atoms, non-limiting examples of which include fluorine atoms (-F) and chlorine atoms (-Cl);
-(CR ^a R ^b ) _z CN;
- ₍ ^CRaRb _)zNO2 ^;
—CH _x X _y (wherein X is a halogen atom and x+y totals 3), non-limiting examples of which include —CH ₂ F, —CHF ₂ , and —CF ₃ ;
—(CR ^a R ^b ) _z C(O)R ^c , non-limiting examples of which include —COCH ₃ , —COCH ₂ CH ₃ , and —CH ₂ COCH ₃ ;
—(CR ^a R ^b ) _z C(O)OR ^c , non-limiting examples include CO ₂ H, —CO ₂ CH ₃ , —CO ₂ CH ₂ CH ₃ , and —CH ₂ CO ₂ CH ₃ be,
—(CR ^a R ^b ) _z C(O)N(R ^c )(R ^d ), non-limiting examples of which include —CONH ₂ , —CONHCH ₃ , —CON(CH ₃ ) ₂ , —CH ₂ CONH ₂ , -CH ₂ CONHCH ₃ , -CH ₂ CON(CH ₃ ) ₂ ;
—(CR ^a R ^b ) _z SO ₂ R ^c ; non-limiting examples thereof include —SO ₂ H, —SO ₂ CH ₃ , —CH ₂ SO ₂ H, —CH ₂ SO ₂ CH ₃ , —SO and -- ₍ CR ^a R _b ⁾ _z SO ₃ R ^c ; non _- limiting examples _thereof include _{--SO 3} H _{, --SO 3} CH ₃ , —CH ₂ SO ₃ H, —CH ₂ SO ₃ CH ₃ , —SO ₃ C ₆ H ₅ , and —CH ₂ SO ₃ C ₆ H ₅ ;
there is
wherein each of R ^a and R ^b is independently selected from hydrogen and substituted or unsubstituted C ₁ -C ₆ linear, branched, or cyclic alkyl; and each of R ^c and R ^d is hydrogen , substituted or unsubstituted C ₁ -C ₆ linear, branched or cyclic alkyl, and aryl, or R ^c and R ^d together form a ring system containing 3 to 7 atoms. and z is selected from 0, 1, 2, 3, and 4.

As used herein, the term "pharmaceutical composition" is in a form such that the biological activity of the active ingredients is effective and is unacceptably toxic to the subject to whom the composition will be administered. It refers to preparations without additional ingredients. In some embodiments, such compositions may be sterile.

The term "pharmaceutically acceptable" as used herein in "pharmaceutically acceptable salts" and "pharmaceutically acceptable excipients" means, within the scope of sound medical judgment, It refers to ingredients that are suitable for use in contact with human and other mammalian tissues without irritation, allergic reactions, etc., and that are commensurate with a reasonable benefit/risk ratio.

The phrase "pharmaceutically acceptable excipient" includes solvents, dispersion media, diluents, dispersants, suspending aids, surfactants, isotonic agents, thickeners or emulsifiers, preservatives, polymers, peptides, Used herein to refer to pharmaceutically acceptable materials selected from proteins, cells, hyaluronidases, and mixtures thereof. In some embodiments, the solvent is an aqueous solvent.

"Treatment," "treating," and "treating" refer to reversing, alleviating (e.g., alleviating one or more symptoms) the condition or disorder described herein, and/or It means to delay its progress.

The terms "disease" and "disorder" are used interchangeably herein to disrupt or interfere with the performance of a function and/or cause discomfort, dysfunction, distress, etc., to the afflicted person or those in contact with the person. Any change in the condition of a part of the body or an organ that causes symptoms of disease or even death. A disease or disorder may be a distemper, ailing, ailment, malady, sickness, illness, complaint, indisposition, or disease (affection) may also be related.

As used herein, "subject" refers to animal subjects, such as mammalian subjects, and particularly humans.

As used herein, the term “administering” refers to administration of a compound, salt, and/or composition by a method or route that results in at least partial localization of the compound, salt, and/or composition at a desired site or tissue location. , a pharmaceutically acceptable salt thereof, and/or a pharmaceutical composition, into a mammalian tissue or subject.

As used herein, the term "therapeutically effective amount" refers to the desired effect for which it is administered (e.g., amelioration of symptoms of a disease or condition mediated by AhR signaling, refers to the amount of compound or salt that produces a reduction in the severity of the condition or its symptoms, and/or a reduction in the progression of any one of the above. The precise amount of an effective dose will depend on the therapeutic objectives and can be ascertained by those skilled in the art using known techniques (see, e.g., Lloyd (1999) The Art, Science and Technology of Pharmaceutical Compounding). ).

A person skilled in the art will recognize that when an amount of a compound is disclosed, a relevant amount of a pharmaceutically acceptable salt form of the compound is an amount equivalent to the amount of the free base of the compound. The amounts of compounds and pharmaceutically acceptable salts disclosed herein are based on the free base form of the relevant compound. For example, "10 mg of at least one entity selected from compounds of formula I or Ia and pharmaceutically acceptable salts thereof" refers to 10 mg of a compound of formula I or Ia or 10 mg of a related compound of formula I or Ia Refers to a pharmaceutically acceptable salt of a compound of Formula I or Ia in an amount equivalent to the compound.

The "efficacy" of a compound or composition of the disclosure can be assessed by any method known to those of skill in the art, including those described in the Examples of the disclosure. Efficacy can be established in vitro (biochemically and/or biologically in cultured cells) and/or in vivo. In vitro efficacy can be used to extrapolate or predict some in vivo efficacy in animals or in human subjects. References or standards or comparisons may be used. The term "effective" in inhibiting signaling mediated by receptors (such as AhR) and/or enzymes in the context of the present disclosure and claims includes the activation of downstream molecules or known biological By effect, it is meant to decrease/activate receptor activity and/or signaling pathway activation and propagation by a detectable or measurable amount relative to baseline activity. This can be assessed in vitro or in vivo, and possibly extrapolated by those skilled in the art to the extent that the activity or benefit may be in vivo. In some embodiments, the reduction or activation is, for example, at least 5%, at least 10%, 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, Measured in percentage reduction or activation relative to activity in the absence of exposure to a compound of the disclosure, including at least 90%, or about 100%. Activity can also fall within a range, eg, 5-10%, 10-20%, and any other range interval between 1% and 100%. An amount is "effective" in vivo if it produces some benefit to the subject to whom the compound or salt is administered.

及びその薬学的に許容できる塩が本明細書に開示される
（式中：
Ｒ^１及びＲ^２のそれぞれは、任意選択で置換されたアルキル、任意選択で置換されたエステル、任意選択で置換されたヘテロアルキル、任意選択で置換されたアシル、任意選択で置換されたアミド、任意選択で置換されたアリール、任意選択で置換されたヘテロアリール、任意選択で置換されたシクロアルキル、任意選択で置換されたアミン、及び任意選択で置換されたヘテロシクロアルキルから独立に選択され；且つ
Ｒ^３は、水素、任意選択で置換されたアルキル、任意選択で置換されたアシル、任意選択で置換されたアミド、任意選択で置換されたアリール、任意選択で置換されたシクロアルキル、任意選択で置換されたエステル、任意選択で置換されたヘテロアルキル、任意選択で置換されたヘテロアリール、任意選択で置換されたヘテロシクロアルキル、任意選択で置換されたアミン、シアノ、ハロ、ヒドロキシ、及び－Ｃ（Ｏ）Ｈから独立に選択される）。 Compounds of formula (I):

and pharmaceutically acceptable salts thereof are disclosed herein, wherein:
each of R ¹ and R ² is optionally substituted alkyl, optionally substituted ester, optionally substituted heteroalkyl, optionally substituted acyl, optionally substituted amide, independently selected from optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted amine, and optionally substituted heterocycloalkyl; and R ³ is hydrogen, optionally substituted alkyl, optionally substituted acyl, optionally substituted amido, optionally substituted aryl, optionally substituted cycloalkyl, optionally optionally substituted heteroalkyl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, optionally substituted amine, cyano, halo, hydroxy, and — independently selected from C(O)H).

In some embodiments, ^R2 is a dialkylamine. In some embodiments, ^R2 is diethylamine.

及びその薬学的に許容できる塩も本明細書に開示される
（式中：
環Ａは、任意選択で置換されたアリール、任意選択で置換されたヘテロアリール、任意選択で置換されたシクロアルキル、及び任意選択で置換されたヘテロシクロアルキルから選択され；
環Ｂは、任意選択で置換されたアリール、任意選択で置換されたヘテロアリール、任意選択で置換されたシクロアルキル、及び任意選択で置換されたヘテロシクロアルキルから選択され；且つ
Ｒは、水素、任意選択で置換されたアルキル、任意選択で置換されたアシル、任意選択で置換されたアミド、任意選択で置換されたアリール、任意選択で置換されたシクロアルキル、任意選択で置換されたエステル、任意選択で置換されたヘテロアルキル、任意選択で置換されたヘテロアリール、任意選択で置換されたヘテロシクロアルキル、アミノ、シアノ、ハロ、ヒドロキシ、及び－Ｃ（Ｏ）Ｈから選択される）。 Compounds of Formula Ia:

and pharmaceutically acceptable salts thereof are also disclosed herein, wherein:
Ring A is selected from optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, and optionally substituted heterocycloalkyl;
Ring B is selected from optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, and optionally substituted heterocycloalkyl; and R is hydrogen; optionally substituted alkyl, optionally substituted acyl, optionally substituted amide, optionally substituted aryl, optionally substituted cycloalkyl, optionally substituted ester, optional optionally substituted heteroalkyl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, amino, cyano, halo, hydroxy, and -C(O)H).

In some embodiments, Ring A is selected from 6-10 membered aryl, 5-10 membered heteroaryl, 3-10 membered cycloalkyl, and 3-10 membered heterocycloalkyl, wherein each 6-10 membered aryl, 5- to 10-membered heteroaryl, 3- to 10-membered cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted independently by 1 to 5 instances of R ^A there is

In some embodiments, Ring B is selected from 6-10 membered aryl, 5-10 membered heteroaryl, 3-10 membered cycloalkyl, and 3-10 membered heterocycloalkyl, wherein each 6-10 Membered aryl, 5-10 membered heteroaryl, 3-10 membered cycloalkyl, and 3-10 membered heterocycloalkyl are optionally substituted independently with 1-5 instances of R 1 ^B.

In some embodiments, R is hydrogen, C ₁ -C ₁₀ alkyl, 6-10 membered aryl, —C(O)R′, —C(O)NR′R′, 3-10 membered cycloalkyl, selected from —C(O)OR′, C ₁ -C ₁₀ heteroalkyl, 5-10 membered heteroaryl, 3-10 membered heterocycloalkyl, amino, cyano, halo, hydroxy, and —C(O)H; wherein each C ₁ -C ₁₀ alkyl, 6-10 membered aryl, 3-10 membered cycloalkyl, C ₁ -C ₁₀ heteroalkyl, 5-10 membered heteroaryl, and 3-10 membered heterocycloalkyl is ~5 instances of ^R 1 independently optionally substituted.

_In some embodiments, each R' is independently selected from hydrogen, C1 _- C10 alkyl, C1 _{- C10} haloalkyl, C1 _{- C10} hydroxyalkyl, and C1 _{- C10} heteroalkyl .

In some embodiments, each R ^A is halo, hydroxy, C ₁ -C ₁₀ alkyl, C ₁ -C ₁₀ haloalkyl, C ₁ -C ₁₀ alkoxy, C ₁ -C ₁₀ haloalkoxy, C ₁ -C ₁₀ independently selected from hydroxyalkyl, and NR''R'';

In some embodiments, each R ^B is halo, hydroxy, C ₁ -C ₁₀ alkyl, C ₁ -C ₁₀ haloalkyl, C ₁ -C ₁₀ alkoxy, C ₁ -C ₁₀ haloalkoxy, C ₁ -C ₁₀ independently selected from hydroxyalkyl, and NR''R'';

In some embodiments, each R ^C is halo, hydroxy, cyano, C ₁ -C ₁₀ alkyl, C ₁ -C ₁₀ alkoxy, C ₁ -C ₁₀ haloalkyl, 3-10 membered cycloalkyl, 3-10 membered independently selected from heterocycloalkyl, 6-10 membered aryl, and 5-10 membered heteroaryl;

In some embodiments, each R″ is independently selected from hydrogen, C ₁ -C ₁₀ alkyl, C ₁ -C ₁₀ haloalkyl, C ₁ -C ₁₀ hydroxyalkyl, and C ₁ -C ₁₀ heteroalkyl. be.

In some embodiments, Ring A is selected from 6-10 membered aryl, 5-8 membered heteroaryl, 3-10 membered cycloalkyl, and 3-10 membered heterocycloalkyl, wherein each 6-10 membered aryl, 5-10 membered heteroaryl, 3-10 membered cycloalkyl, and 3-10 membered heterocycloalkyl are optionally substituted independently with 1-5 instances of R ^A ;
Ring B is selected from 6-10 membered aryl, 5-10 membered heteroaryl, 3-10 membered cycloalkyl, and 3-10 membered heterocycloalkyl, wherein each 6-10 membered aryl, 5-10 membered heteroaryl, 3-10 membered cycloalkyl, and 3-10 membered heterocycloalkyl are optionally substituted independently with 1-5 instances of R ^B ;
R is hydrogen, C ₁ -C ₁₀ alkyl, 6-10 membered aryl, —C(O)R′, —C(O)NR′R′, 3-10 membered cycloalkyl, —C(O)OR′ , C ₁ -C ₁₀ heteroalkyl, 5-10 membered heteroaryl, 3-10 membered heterocycloalkyl, amino, cyano, halo, hydroxy, and —C(O)H, wherein each C ₁ - C ₁₀ alkyl, 6-10 membered aryl, 3-10 membered cycloalkyl, C ₁ -C ₁₀ heteroalkyl, 5-10 membered heteroaryl, and 3-10 membered heterocycloalkyl are represented by 1-5 examples of ^R independently optionally substituted;
each R′ is independently selected from hydrogen, C ₁ -C ₁₀ alkyl, C ₁ -C ₁₀ haloalkyl, C ₁ -C ₁₀ hydroxyalkyl, and C ₁ -C ₁₀ heteroalkyl;
Each R ^A is halo, hydroxy, C ₁ -C ₁₀ alkyl, C ₁ -C ₁₀ haloalkyl, C ₁ -C ₁₀ alkoxy, C ₁ -C ₁₀ haloalkoxy, C ₁ -C ₁₀ hydroxyalkyl, and NR″ independently selected from R'';
Each R ^B is halo, hydroxy, C ₁ -C ₁₀ alkyl, C ₁ -C ₁₀ haloalkyl, C ₁ -C ₁₀ alkoxy, C ₁ -C ₁₀ haloalkoxy, C ₁ -C ₁₀ hydroxyalkyl, and NR″ independently selected from R'';
Each R ^C is halo, hydroxy, cyano, C ₁ -C ₁₀ alkyl, C ₁ -C ₁₀ alkoxy, C ₁ -C ₁₀ haloalkyl, 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, 6-10 independently selected from 5- to 10-membered heteroaryl; and each R″ is hydrogen, C ₁ -C ₁₀ alkyl, C ₁ -C ₁₀ haloalkyl, C ₁ -C ₁₀ hydroxyalkyl, and C ₁ independently selected from _-C10 heteroalkyl;

In some embodiments, Ring ^A is selected from 3-10 membered cycloalkyl optionally substituted with 1-5 instances of RA. In some embodiments, Ring A is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl optionally substituted with 1-5 instances of R ^A. In some embodiments, Ring ^A is selected from 6-8 membered aryl optionally substituted with 1-5 instances of RA. In some embodiments, Ring ^A is phenyl optionally substituted with 1-3 instances of RA. In some embodiments, Ring ^A is selected from 5-8 membered heteroaryl optionally substituted with 1-5 instances of RA.

In some embodiments, Ring A is selected from pyrrolyl, furanyl, furazanyl, thiophenyl, imidazolyl, isothiazolyl, isoxazolyl, oxazolyl, oxadiazolyl, tetrazolyl, thiazolyl, triazolyl, pyrazolyl, pyridinyl, pyrazinyl, pyridazinyl, and pyrimidinyl wherein pyrrolyl, furanyl, furazanyl, thiophenyl, imidazolyl, isothiazolyl, isoxazolyl, oxazolyl, oxadiazolyl, tetrazolyl, thiazolyl, triazolyl, pyrazolyl, pyridinyl, pyrazinyl, pyridazinyl, and pyrimidinyl are each represented by one to three instances of R ^A optionally substituted independently by

In some embodiments, Ring ^A is pyridinyl optionally substituted with 1-3 instances of RA. In some embodiments, Ring ^A is selected from 5-8 membered heterocycloalkyl optionally substituted with 1-5 instances of RA. In some embodiments, Ring A is selected from pyrrolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, morpholino, azepinyl, tetrahydropyranyl, and tetrahydrofuranyl, wherein pyrrolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, morpholino, azepinyl, tetrahydro Each of pyranyl and tetrahydrofuranyl is independently optionally substituted with 1-3 instances of R 1 ^A. In some embodiments, Ring ^A is piperidinyl or morpholino optionally substituted with 1-3 instances of RA.

In some embodiments, each R ^A is halo, C ₁ -C ₁₀ alkyl, C ₁ -C ₁₀ haloalkyl, C ₁ -C ₁₀ alkoxy, C ₁ -C ₁₀ haloalkoxy, and NR″R″ independently selected from In some embodiments, each R ^B is independently selected from halo, C ₁ -C ₁₀ alkyl, and C ₁ -C ₁₀ haloalkyl. In some embodiments, each R ^C is halo, hydroxy, cyano, C ₁ -C ₁₀ alkyl, C ₁ -C ₁₀ alkoxy, 3-8 membered cycloalkyl, 3-8 membered heterocycloalkyl, and 6- independently selected from 8-membered aryl; In some embodiments, each R'' is independently selected from hydrogen and C1 _{- C10} alkyl.

In some embodiments, each R ^A is halo, C ₁ -C ₁₀ alkyl, C ₁ -C ₁₀ haloalkyl, C ₁ -C ₁₀ alkoxy, C ₁ -C ₁₀ haloalkoxy, and NR″R″ independently selected from;
each R ^B is independently selected from halo, C ₁ -C ₁₀ alkyl, and C ₁ -C ₁₀ haloalkyl;
each R ^C is independently selected from halo, hydroxy, cyano, C ₁ -C ₁₀ alkyl, C ₁ -C ₁₀ alkoxy, 3-8 membered cycloalkyl, 3-8 membered heterocycloalkyl, and 6-8 membered aryl and each R″ is independently selected from hydrogen and C ₁ -C ₁₀ alkyl.

In some embodiments, ring ^B is selected from 6-8 membered aryl optionally substituted with 1-5 instances of RB. In some embodiments, ring B is phenyl optionally substituted with 1-3 instances of R 1 ^B. In some embodiments, ring B is selected from 5-8 membered heteroaryl optionally substituted with 1-5 instances of R ^B . In some embodiments, Ring B is selected from pyrrolyl, furanyl, furazanyl, thiophenyl, imidazolyl, isothiazolyl, isoxazolyl, oxazolyl, oxadiazolyl, tetrazolyl, thiazolyl, triazolyl, pyrazolyl, pyridinyl, pyrazinyl, pyridazinyl, pyridinonyl, and pyrimidinyl , wherein pyrrolyl, furanyl, furazanyl, thiophenyl, imidazolyl, isothiazolyl, isoxazolyl, oxazolyl, oxadiazolyl, tetrazolyl, thiazolyl, triazolyl, pyrazolyl, pyridinyl, pyrazinyl, pyridazinyl, and pyrimidinyl are each represented by one to three instances of R ^B independently optionally substituted. In some embodiments, Ring B is selected from pyrazolyl, isothiazolyl, isoxazolyl, pyridinyl, pyrimidinyl, and thiophenyl, wherein each of pyrazolyl, isothiazolyl, isoxazolyl, pyridinyl, pyrimidinyl, and thiophenyl is 1-3 examples. is optionally substituted independently with R ^B of .

から選択される。 In some embodiments, Ring A is

is selected from

から選択される。 In some embodiments, Ring A is

is selected from

から選択される。 In some embodiments, Ring A is

is selected from

から選択される。 In some embodiments, Ring B is

is selected from

からである（ｉｓ ｆｒｏｍ）。 In some embodiments, Ring B is

is from.

から選択される。 In some embodiments, Ring B is

is selected from

から選択される。 In some embodiments, R is methyl,

is selected from

から選択される。 In some embodiments, R is methyl,

is selected from

及びその薬学的に許容できる塩も本明細書に開示される
（式中：
環Ａは、任意選択で置換されたヘテロアリール及び任意選択で置換されたヘテロシクロアルキルから選択され；
環Ｂは、任意選択で置換されたヘテロアリール及び任意選択で置換されたヘテロシクロアルキルから選択され；且つ
Ｒは、水素、任意選択で置換されたアルキル、任意選択で置換されたアシル、任意選択で置換されたアミド、任意選択で置換されたアリール、任意選択で置換されたシクロアルキル、任意選択で置換されたエステル、任意選択で置換されたヘテロアルキル、任意選択で置換されたヘテロアリール、任意選択で置換されたヘテロシクロアルキル、アミノ、シアノ、ハロ、ヒドロキシ、及び－Ｃ（Ｏ）Ｈから選択される）。 Compounds of Formula Ib:

and pharmaceutically acceptable salts thereof are also disclosed herein, wherein:
Ring A is selected from optionally substituted heteroaryl and optionally substituted heterocycloalkyl;
Ring B is selected from optionally substituted heteroaryl and optionally substituted heterocycloalkyl; and R is hydrogen, optionally substituted alkyl, optionally substituted acyl, optionally amido substituted with, optionally substituted aryl, optionally substituted cycloalkyl, optionally substituted ester, optionally substituted heteroalkyl, optionally substituted heteroaryl, optionally optionally substituted heterocycloalkyl, amino, cyano, halo, hydroxy, and -C(O)H).

In some embodiments, the disclosure relates to one or more compounds listed in Table 1.

In some embodiments, the present disclosure relates to one or more compounds selected from the following compounds and pharmaceutically acceptable salts thereof:
(i) (S)-8-(5-fluoropyridin-3-yl)-3-(1-hydroxypropan-2-yl)-6-(4-(trifluoromethoxy)phenyl)pyrido[3,4 -d]pyrimidin-4(3H)-one;
(ii) (S)-6-(4-chlorophenyl)-3-(1-hydroxypropan-2-yl)-8-(6-oxo-1,6-dihydropyridin-3-yl)pyrido[3,4 -d]pyrimidin-4(3H)-one;
(iii) (S)-8-(benzo[d][1,3]dioxol-4-yl)-6-(4-chlorophenyl)-3-(1-hydroxypropan-2-yl)pyrido[3, 4-d]pyrimidin-4(3H)-one;
(iv) (S)-3-(1-hydroxypropan-2-yl)-8-(pyridin-4-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido [3, 4-d]pyrimidin-4(3H)-one;
(v) (S)-8-(5-fluoropyridin-3-yl)-3-(1-hydroxypropan-2-yl)-6-(4-(trifluoromethyl)phenyl)pyrido[3,4 -d]pyrimidin-4(3H)-one;
(vi) (S)-3-(1-hydroxypropan-2-yl)-6,8-di(pyridin-4-yl)pyrido[3,4-d]pyrimidin-4(3H)-one;
(vii) (S)-6-(4-chlorophenyl)-8-(3-fluorophenyl)-3-(1-hydroxypropan-2-yl)pyrido[3,4-d]pyrimidine-4(3H) -on;
(viii) (S)-8-(3-fluorophenyl)-3-(1-hydroxypropan-2-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4 -d]pyrimidin-4(3H)-one;
(ix) 3-(2-hydroxy-2-methylpropyl)-8-(pyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d] pyrimidin-4(3H)-one;
(x) 6,8-di(pyridin-3-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)pyrido[3,4-d]pyrimidin-4(3H)-one;
(xi) (S)-6-chloro-3-(1-hydroxypropan-2-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one;
(xii) (S)-3-(1-hydroxypropan-2-yl)-8-(pyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido [3, 4-d]pyrimidin-4(3H)-one;
(xiii) 6-(4-chlorophenyl)-8-(pyridin-3-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)pyrido[3,4-d]pyrimidine-4 ( 3H)—on;
(xiv) 8-(pyridin-3-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)-6-(4-(trifluoromethoxy)phenyl)pyrido[3,4-d ] pyrimidin-4(3H)-one;
(xv) 6-(4-chlorophenyl)-8-(1-methyl-1H-pyrazol-4-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)pyrido[3,4- d] pyrimidin-4(3H)-one;
(xvi) 3-(2-hydroxy-2-methylpropyl)-8-(pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyrimidine-4 ( 3H)—on;
(xvii) (S)-3-(1-hydroxypropan-2-yl)-8-(pyridin-3-yl)-6-(p-tolyl)pyrido[3,4-d]pyrimidine-4(3H )-on;
(xviii) 6-(4-chlorophenyl)-3-(2-hydroxy-2-methylpropyl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one;
(xix) 3-(2-hydroxy-2-methylpropyl)-6,8-bis(1-methyl-1H-pyrazol-4-yl)pyrido[3,4-d]pyrimidin-4(3H)-one ;
(xx) (S)-3-(1-hydroxypropan-2-yl)-6,8-di(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one;
(xxi) 6-(4-chlorophenyl)-3-(2-hydroxy-2-methylpropyl)-8-(1-methyl-1H-pyrazol-4-yl)pyrido[3,4-d]pyrimidine-4 (3H)-on;
(xxii) (S)-3-(1-hydroxypropan-2-yl)-8-(pyridin-3-yl)-6-(4-(trifluoromethoxy)phenyl)pyrido[3,4-d] pyrimidin-4(3H)-one;
(xxiii) (S)-3-(1-hydroxypropan-2-yl)-8-(pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrido[3,4-d] pyrimidin-4(3H)-one;
(xxiv) (S)-6-(4-chlorophenyl)-3-(1-hydroxypropan-2-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidine-4(3H )-on;
(xxv) (S)-3-(1-hydroxypropan-2-yl)-8-(1-methyl-1H-pyrazol-4-yl)-6-(4-(trifluoromethoxy)phenyl)pyrido [ 3,4-d]pyrimidin-4(3H)-one;
(xxvi) (S)-3-(1-hydroxypropan-2-yl)-8-(1-methyl-1H-pyrazol-4-yl)-6-phenylpyrido[3,4-d]pyrimidine-4 ( 3H)—on;
(xxvii) (S)-6-(4-chlorophenyl)-3-(1-hydroxypropan-2-yl)-8-(1-methyl-1H-pyrazol-4-yl)pyrido [3,4-d ] pyrimidin-4(3H)-one;
(xxviii) 3-methyl-8-(pyridin-3-yl)-6-(4-(trifluoromethoxy)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one;
(xxix) Rac-6-(4-chlorophenyl)-3-((trans)-4-hydroxytetrahydrofuran-3-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidine-4 (3H)-on;
(xxx) (S)-6-(4-chlorophenyl)-3-(3-hydroxy-3-methylbutan-2-yl)-8-(1-methyl-1H-pyrazol-4-yl)pyrido [3, 4-d]pyrimidin-4(3H)-one;
(xxxi) (R)-6-(4-chlorophenyl)-3-(3-hydroxy-3-methylbutan-2-yl)-8-(1-methyl-1H-pyrazol-4-yl)pyrido [3, 4-d]pyrimidin-4(3H)-one;
(xxxii) rac-6-(4-chlorophenyl)-3-((cis)-4-hydroxytetrahydrofuran-3-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidine-4 (3H)-on;
(xxxiii) (R)-6-(4-chlorophenyl)-3-(3-hydroxy-3-methylbutan-2-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidine- 4(3H)-on;
(xxxiv) (S)-3-(3-hydroxy-3-methylbutan-2-yl)-6,8-di(pyridin-3-yl)pyrido[3,4-d]pyrimidine-4(3H)- on;
(xxxv) (S)-6,8-bis(3,5-difluorophenyl)-3-(1-hydroxy-3-methylbutan-2-yl)pyrido[3,4-d]pyrimidine-4(3H) -on;
(xxxvi) (S)-6-(4-chlorophenyl)-3-(3-hydroxy-3-methylbutan-2-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidine- 4(3H)-on;
(xxxvii) (S)-8-(3,5-difluorophenyl)-3-(1-hydroxy-3-methylbutan-2-yl)-6-(p-tolyl)pyrido[3,4-d]pyrimidine -4(3H)-one;
(xxxviii) 6-(4-chlorophenyl)-8-(3-fluorophenyl)-3-(2-hydroxy-2-methylpropyl)pyrido[3,4-d]pyrimidin-4(3H)-one;
(xxxix) (R)-6-(4-chlorophenyl)-8-(3-fluorophenyl)-3-(3-hydroxy-3-methylbutan-2-yl)pyrido[3,4-d]pyrimidine-4 (3H)-on;
(xl) (S)-3-(1-(benzyloxy)propan-2-yl)-8-(3-fluorophenyl)-6-(p-tolyl)pyrido[3,4-d]pyrimidine-4 (3H)-on;
(xli) (R)-6-(4-chlorophenyl)-8-(3-fluorophenyl)-3-(3,3,3-trifluoro-2-hydroxypropyl)pyrido[3,4-d]pyrimidine -4(3H)-one;
(xlii) (S)-6-(4-chlorophenyl)-8-(3-fluorophenyl)-3-(3,3,3-trifluoro-2-hydroxypropyl)pyrido[3,4-d]pyrimidine -4(3H)-one;
(xliii) (S)-3-(1-hydroxypropan-2-yl)-6-morpholin-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one;
(xliv) (S)-3-(1-hydroxypropan-2-yl)-8-(1H-imidazol-1-yl)-6-(4-(trifluoromethoxy)phenyl)pyrido[3,4- d] pyrimidin-4(3H)-one;
(xlv) (S)-3-(1-methoxypropan-2-yl)-8-(pyridin-3-yl)-6-(p-tolyl)pyrido[3,4-d]pyrimidine-4 (3H )-on;
(xlvi) (S)-3-(1-hydroxypropan-2-yl)-8-(pyridin-3-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido [3, 4-d]pyrimidin-4(3H)-one;
(xlvii) (S)-8-(3-fluorophenyl)-3-(1-hydroxypropan-2-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4 -d]pyrimidin-4(3H)-one;
(xlviii) (S)-8-(3-fluorophenyl)-3-(1-hydroxypropan-2-yl)-6-(p-tolyl)pyrido[3,4-d]pyrimidine-4(3H) -on;
(xlix) (S)-8-(3-fluorophenyl)-3-(1-hydroxypropan-2-yl)-6-(4-(trifluoromethoxy)phenyl)pyrido[3,4-d]pyrimidine -4(3H)-one;
(l) (S)-3-(1-hydroxypropan-2-yl)-8-(pyridin-3-yl)-6-(6-(trifluoromethoxy)pyridin-3-yl)pyrido [3, 4-d]pyrimidin-4(3H)-one (li)(S)-3-(2-hydroxy-2-methylpropyl)-8-(1H-pyrazol-4-yl)-6-(6-( trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (lii)methyl (S)-5-(3-(1-hydroxypropan-2-yl)- 4-oxo-8-(pyridin-3-yl)-3,4-dihydropyrido[3,4-d]pyrimidin-6-yl)picolinate (liii) (S)-3-(1-hydroxypropane-2- yl)-6-(isothiazol-4-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (liv) 3-(2-hydroxy-2 -methylpropyl)-8-(isothiazol-4-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (lv ) (S)-3-(1-hydroxypropan-2-yl)-8-(isothiazol-4-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido [3,4 -d]pyrimidin-4(3H)-one (lvi)(S)-3-(1-hydroxypropan-2-yl)-6,8-di(isothiazol-4-yl)pyrido[3,4- d]pyrimidin-4(3H)-one (lvii)(S)-8-(pyridin-3-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)-6-(6- (trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (lviii) (S)-6-(4-chlorophenyl)-3-(1-hydroxypropane- 2-yl)-8-(isothiazol-4-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (lix) 3-(2-hydroxy-2-methylpropyl)-6,8 -di(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (lx) 3-(2-hydroxy-2-methylpropyl)-8-(1-methyl-1H- pyrazol-4-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (lxi) 6-(4-chloro- 2-methylphenyl)-3-(2-hydroxy-2-methylpropyl)-8-(1-methyl-1H-pyrazol-4-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (lxii) (S)-3-(1-hydroxypropan-2-yl)-8-(1H-pyrazol-4-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido [ 3,4-d]pyrimidin-4(3H)-one (lxiii) (S)-3-(1-hydroxypropan-2-yl)-8-(2-methylpyridin-3-yl)-6-( 6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (lxiv) (S)-3-(1-hydroxypropan-2-yl)-8 -(4-methylpyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (lxv) (S) -3-(1-hydroxypropan-2-yl)-6-(4-methylthiazol-5-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidine-4(3H) -one (lxvi) (S)-6-(2-cyclopropylthiazol-5-yl)-3-(1-hydroxypropan-2-yl)-8-(pyridin-3-yl)pyrido[3,4 -d]pyrimidin-4(3H)-one (lxvii) (S)-3-(1-hydroxypropan-2-yl)-6-(2-isopropylthiazol-5-yl)-8-(pyridin-3 -yl)pyrido[3,4-d]pyrimidin-4(3H)-one (lxviii) (S)-3-(1-hydroxypropan-2-yl)-8-(1-methyl-1H-pyrazole- 4-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (lxix)(S)-3-(1-hydroxy propan-2-yl)-6,8-bis(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (lxx)6-(4- Chlorophenyl)-3-((3S,4S)-4-hydroxytetrahydrofuran-3-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (lxxi) 6-(4-chlorophenyl)-3-((3R,4R)-4-hydroxytetrahydrofuran-3-yl)-8-(pyridin-3-yl) pyrido[3,4-d]pyrimidin-4(3H)-one (lxxii) 3-(2-hydroxyethyl)-8-(pyridin-3-yl)-6-(4-(trifluoromethoxy)phenyl) pyrido[3,4-d]pyrimidin-4(3H)-one (lxxiii)(S)-6-(4-chlorophenyl)-3-(1-hydroxypropan-2-yl)-8-(1-methyl -6-oxo-1,6-dihydropyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (lxxiv)(S)-6-(6-cyclopropylpyridin-3-yl )-3-(1-hydroxypropan-2-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (lxxv)(S)-3-( 1-hydroxypropan-2-yl)-6-(4-methyl-6-(trifluoromethyl)pyridin-3-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidine- 4(3H)-one (lxxvi)(S)-3-(1-hydroxypropan-2-yl)-8-(1-methyl-1H-pyrazol-4-yl)-6-(pyridin-3-yl ) pyrido[3,4-d]pyrimidin-4(3H)-one (lxxvii) (S)-6-(cyclohex-1-en-1-yl)-3-(1-hydroxypropan-2-yl) -8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (lxxviii)(S)-6,8-bis(5-fluoropyridin-3-yl)-3 -(1-hydroxypropan-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (lxxix)3-((3R,4S)-4-hydroxytetrahydrofuran-3-yl)-8 -(pyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (lxxx)3-(2-hydroxy -2-methylpropyl)-8-(pyridin-3-yl)-6-(2-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one ( lxxxi) 6-(6-cyclopropylpyridin-3-yl)-3-(2-hydroxy-2-methylpropyl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidine-4 ( 3H)-one (lxxxii) 6-(6-cyclopropylpyridin-3-yl)-3-(2-hydroxy-2-methyl propyl)-8-(1-methyl-1H-pyrazol-4-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (lxxxiii)(S)-6-(6-cyclopropylpyridine- 3-yl)-3-(1-hydroxypropan-2-yl)-8-(1-methyl-1H-pyrazol-4-yl)pyrido[3,4-d]pyrimidin-4(3H)-one ( lxxxiv) (S)-3-(1-hydroxypropan-2-yl)-8-(pyridin-3-yl)-6-(thiazol-5-yl)pyrido[3,4-d]pyrimidine-4 ( 3H)-one (lxxxv)(S)-3-(1-hydroxypropan-2-yl)-8-(pyridin-3-yl)-6-(2-(trifluoromethyl)thiazol-5-yl) pyrido[3,4-d]pyrimidin-4(3H)-one (lxxxvi)(S)-3-(1-hydroxypropan-2-yl)-8-(pyridin-3-yl)-6-(2 -(trifluoromethyl)pyrimidin-5-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (lxxxvii) 3-(2-hydroxy-2-methylpropyl)-8-(pyridine-3 -yl)-6-(2-(trifluoromethyl)thiazol-5-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (lxxxviii)3-((3S,4S)-4- Hydroxytetrahydrofuran-3-yl)-8-(1-methyl-1H-pyrazol-4-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidine- 4(3H)-one (lxxxix)(S)-3-(1-hydroxypropan-2-yl)-6-(2-methylthiazol-5-yl)-8-(pyridin-3-yl)pyrido [ 3,4-d]pyrimidin-4(3H)-one (xc)(S)-6-(4-chlorophenyl)-8-(3-fluorophenyl)-3-(1-hydroxy-3-methylbutane-2 -yl)pyrido[3,4-d]pyrimidin-4(3H)-one (xci)(S)-3-(1-hydroxypropan-2-yl)-6-(piperidin-1-yl)-8 -(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (xcii) 3-(2-hydroxy-2-methylpropyl)-8-(isothiazol-4-yl) -6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidine-4(3 H)-one (xciii) (S)-3-(1-hydroxypropan-2-yl)-8-(isothiazol-4-yl)-6-(5-(trifluoromethyl)pyridin-2-yl ) pyrido[3,4-d]pyrimidin-4(3H)-one (xciv) 3-(2-hydroxy-2-methylpropyl)-8-(1-methyl-1H-pyrazol-4-yl)-6 -(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (xcv)(S)-8-(pyridin-3-yl)-3- (3,3,3-trifluoro-2-hydroxypropyl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (xcvi ) (3-(2-hydroxy-2-methylpropyl)-8-(pyridin-3-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidine -4(3H)-one (xcvii) 3-(1,1-dioxidotetrahydrothiophen-3-yl)-8-(pyridin-3-yl)-6-(6-(trifluoromethyl)pyridine-3 -yl)pyrido[3,4-d]pyrimidin-4(3H)-one (xcviii) (R)-3-(1,1-dioxidotetrahydrothiophen-3-yl)-8-(pyridin-3- yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (xcix) (R)-3-(2-hydroxypropyl) -8-(1-methyl-1H-pyrazol-4-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one ( c) (S)-3-(2-hydroxypropyl)-8-(1-methyl-1H-pyrazol-4-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido [3 ,4-d]pyrimidin-4(3H)-one (ci)(R)-8-(1-methyl-1H-pyrazol-4-yl)-3-(3,3,3-trifluoro-2- Hydroxypropyl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cii)(S)-8-(1-methyl- 1H-pyrazol-4-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)-6-(6-(trifluoromethyl)pyridine-3 -yl)pyrido[3,4-d]pyrimidin-4(3H)-one (ciii) (R)-3-(2-hydroxypropyl)-8-(pyridin-3-yl)-6-(6- (trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (civ) (R)-8-(1-methyl-1H-pyrazol-4-yl)- 3-(3,3,3-trifluoro-2-hydroxypropyl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cv) 3-((3S,4R)-4-hydroxytetrahydrofuran-3-yl)-8-(1-methyl-1H-pyrazol-4-yl)-6-(6-(trifluoromethyl)pyridine- 3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cvi) 3-((3R,4S)-4-hydroxytetrahydrofuran-3-yl)-8-(1-methyl-1H -pyrazol-4-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cvii)6-(4-chlorophenyl) -3-((3S,4R)-4-hydroxytetrahydrofuran-3-yl)-8-(1-methyl-1H-pyrazol-4-yl)pyrido[3,4-d]pyrimidine-4(3H)- On (cviii) 3-((3S,4R)-4-hydroxytetrahydrofuran-3-yl)-8-(pyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido [3,4-d]pyrimidin-4(3H)-one (cix)(S)-6-(6-cyclopropylpyridin-3-yl)-8-(pyridin-3-yl)-3-(3 ,3,3-trifluoro-2-hydroxypropyl)pyrido[3,4-d]pyrimidin-4(3H)-one (cx)(R)-6-(6-cyclopropylpyridin-3-yl)- 8-(pyridin-3-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxi)(R)- 8-(pyridin-3-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido [3,4- d]pyrimidin-4(3H)-one (cxii) (R)-8-(pyridin-3-yl)-3-(3,3,3-trifluoro-2- Hydroxypropyl)-6-(4-(trifluoromethoxy)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxiii)(S)-8-(pyridin-3-yl)-3 -(3,3,3-trifluoro-2-hydroxypropyl)-6-(4-(trifluoromethoxy)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxiv)6- (4-chlorophenyl)-3-((3S,4R)-4-hydroxytetrahydrofuran-3-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxv) 3-((3S,4S)-4-hydroxytetrahydrofuran-3-yl)-8-(pyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido [ 3,4-d]pyrimidin-4(3H)-one (cxvi)methyl (S)-2-(4-oxo-8-(pyridin-3-yl)-6-(6-(trifluoromethyl)pyridine -3-yl)pyrido[3,4-d]pyrimidin-3(4H)-yl)propanoate (cxvii) 6-(4-chlorophenyl)-3-(4-hydroxy-1-methylpyrrolidin-3-yl) -8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxviii)6-(4-chlorophenyl)-3-((3R,4R)-4-hydroxypyrrolidine -3-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxix)(R)-6-(6-cyclopropylpyridin-3-yl )-8-(1-methyl-1H-pyrazol-4-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)pyrido[3,4-d]pyrimidine-4(3H)- On (cxx)(S)-6-(6-cyclopropylpyridin-3-yl)-8-(1-methyl-1H-pyrazol-4-yl)-3-(3,3,3-trifluoro- 2-hydroxypropyl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxxi) 3-((3S,4R)-4-hydroxytetrahydrofuran-3-yl)-8-(1-methyl- 1H-pyrazol-4-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxxii)3-((3R, 4S)-4-hydroxytetrahydrofuran-3-yl)-8-(1-methyl -1H-pyrazol-4-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxxiii)3-((3S , 4R)-4-hydroxytetrahydrofuran-3-yl)-8-(pyridin-3-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidine- 4(3H)-one (cxxiv) 3-((3R,4S)-4-hydroxytetrahydrofuran-3-yl)-8-(pyridin-3-yl)-6-(5-(trifluoromethyl)pyridine- 2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxxv) (R)-3-(2-hydroxypropyl)-8-(1-methyl-1H-pyrazol-4-yl )-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxxvi)(S)-3-(2-hydroxypropyl)- 8-(1-methyl-1H-pyrazol-4-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxxvii ) (S)-3-(2-hydroxypropyl)-8-(pyridin-3-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidine- 4(3H)-one (cxxviii) (R)-3-(2-hydroxypropyl)-8-(pyridin-3-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido [ 3,4-d]pyrimidin-4(3H)-one (cxxix)3-((3S,4S)-4-hydroxytetrahydrofuran-3-yl)-8-(pyridin-3-yl)-6-(5 -(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxxx)(S)-3-(2-hydroxypropyl)-8-(pyridine-3 -yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxxxi)(S)-8-(1-methyl- 1H-pyrazol-4-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido [3,4-d ] pyrimidin-4(3H)-one (cxxxii)(S)-3-(1-hydroxypropane-2 -yl)-8-(1-methyl-1H-pyrazol-4-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidine-4(3H) -one (cxxxiii) 3-((3S,4S)-4-hydroxytetrahydrofuran-3-yl)-8-(1-methyl-1H-pyrazol-4-yl)-6-(5-(trifluoromethyl) pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxxxiv) 6-(4-chlorophenyl)-3-((3R,4S)-4-hydroxytetrahydrofuran-3-yl )-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxxxv)6-(4-chlorophenyl)-3-((3R,4S)-4-hydroxy Tetrahydrofuran-3-yl)-8-(1-methyl-1H-pyrazol-4-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxxxvi) (R)-8-(pyridine- 3-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidine-4 (3H)-one (cxxxvii)(S)-2-(4-oxo-8-(pyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4 -d]pyrimidin-3(4H)-yl)propanoic acid (cxxxviii) (S)-N-methyl-2-(4-oxo-8-(pyridin-3-yl)-6-(6-(trifluoro methyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-3(4H)-yl)propanamide (cxxxix) (S)-N,N-dimethyl-2-(4-oxo-8-( Pyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-3(4H)-yl)propenamide (cxl) 3-(2- Hydroxy-2-methylpropyl)-8-(1H-pyrazol-4-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidine-4(3H) -one (cxli) 3-(2-hydroxy-2-methylpropyl)-8-(1H-imidazol-1-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido [3, 4-d]pyrimidin-4(3H)-one (cxlii) 3-(2-hydroxy -2-methylpropyl)-8-(1H-imidazol-1-yl)-6-(6-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidine-4(3H)- On (cxliii) (S)-3-(1-hydroxypropan-2-yl)-8-(1H-imidazol-1-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido [3,4-d]pyrimidin-4(3H)-one (cxliv) (S)-3-(1-hydroxypropan-2-yl)-8-(1H-imidazol-1-yl)-6-( 6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxlv)(S)-3-(1-hydroxypropan-2-yl)-8 -(1H-1,2,4-triazol-1-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one ( cxlvi) (S)-3-(1-hydroxypropan-2-yl)-8-(1H-pyrazol-1-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido [3 , 4-d]pyrimidin-4(3H)-one (cxlvii) (S)-3-(1-hydroxypropan-2-yl)-8-(1-methyl-1H-pyrazol-4-yl)-6 -(2-(trifluoromethyl)thiazol-5-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxlviii)(S)-8-(diethylamino)-3-(1-hydroxy Propan-2-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxlix)(S)-3-(1 -hydroxypropan-2-yl)-8-(piperidin-1-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidine-4(3H)- On (cl) (S)-3-(1-hydroxypropan-2-yl)-8-(pyrrolidin-1-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido [3 ,4-d]pyrimidin-4(3H)-one (cli)(S)-6-(4-chlorophenyl)-3-(1-hydroxypropan-2-yl)-8-(piperidin-1-yl) pyrido[3,4-d]pyrimidin-4(3H)-one (clii)(S)-3-(1-hydroxypropan-2-yl)-8- (pyridin-2-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cliiii)(S)-6-cyclohexyl -3-(1-hydroxypropan-2-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cliv)(S)-3-(1 -hydroxypropan-2-yl)-6-(pyridin-2-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (clv) (S) -3-(1-hydroxypropan-2-yl)-6-(2-methylthiazol-4-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidine-4(3H) -one (clvi) (S)-3-(1-hydroxypropan-2-yl)-6-(1-methyl-1H-1,2,3-triazol-5-yl)-8-(pyridin-3 -yl)pyrido[3,4-d]pyrimidin-4(3H)-one (clvii)(R)-6-(4-chlorophenyl)-8-(pyridin-3-yl)-3-(3,3 ,3-trifluoro-2-hydroxypropyl)pyrido[3,4-d]pyrimidin-4(3H)-one (clviii) (S)-6-(4-chlorophenyl)-8-(pyridin-3-yl )-3-(3,3,3-trifluoro-2-hydroxypropyl)pyrido[3,4-d]pyrimidin-4(3H)-one (clix) (S)-3-(1-hydroxypropane- 2-yl)-8-(1-methyl-1,2,5,6-tetrahydropyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4- d]pyrimidin-4(3H)-one (clx)6-(4-chlorophenyl)-3-((3S,4S)-4-hydroxytetrahydrofuran-3-yl)-8-(1-methyl-1H-pyrazole -4-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (clxi)(S)-3-(1-hydroxypropan-2-yl)-6-(2-methylpyrimidine-5 -yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (clxii) 3-(2-hydroxy-2-methylpropyl)-8-(1- (trifluoromethyl)-1H-pyrazol-4-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidine-4 ( 3H)-one (clxiii) (S)-3-(1-hydroxypropan-2-yl)-8-(1-methyl-1H-pyrazol-4-yl)-6-(2-(trifluoromethyl) pyrimidin-5-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (clxiv) 3-(2-hydroxy-2-methylpropyl)-8-(pyridin-3-yl)-6- (2-(trifluoromethyl)pyrimidin-5-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (clxv) (S)-5-(3-(1-hydroxypropane-2- yl)-4-oxo-8-(pyridin-3-yl)-3,4-dihydropyrido[3,4-d]pyrimidin-6-yl)picolinic acid (clxvi) (S)-3-(1-hydroxy propan-2-yl)-6-(6-methylpyridin-3-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (clxvii)3- (2-hydroxy-2-methylpropyl)-8-(1-methyl-1H-pyrazol-4-yl)-6-(2-(trifluoromethyl)pyrimidin-5-yl)pyrido [3,4-d ] pyrimidin-4(3H)-one (clxviii) 3,8-di(pyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidine -4(3H)-one (clxix)8-(pyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidine-4(3H) -one (clxx) 3-((3R,4R)-4-hydroxytetrahydrofuran-3-yl)-8-(pyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-3-yl) pyrido[3,4-d]pyrimidin-4(3H)-one (clxxi) 3-((3R,4R)-4-hydroxytetrahydrofuran-3-yl)-8-(1-methyl-1H-pyrazole-4 -yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (clxxii)6-(4-chlorophenyl)-3-( (3R,4R)-4-hydroxytetrahydrofuran-3-yl)-8-(1-methyl-1H-pyrazol-4-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (clxxiii) 3-cyclopentyl-8-(pyridin-3-yl)-6-(6-(trifluoro Luoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (clxxiv) 3-phenyl-8-(pyridin-3-yl)-6-(6-(trifluoromethyl ) pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (clxxv) 3-((3R,4R)-4-hydroxytetrahydrofuran-3-yl)-8-(pyridine- 3-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (clxxvi)3-((3R,4R)-4 -hydroxytetrahydrofuran-3-yl)-8-(1-methyl-1H-pyrazol-4-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidine -4(3H)-one (clxxvii) (S)-3-(1-hydroxypropan-2-yl)-8-(1-methyl-1H-pyrazol-4-yl)-6-(5-(tri fluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (clxxviii)(S)-N-((3R,4S)-4-hydroxytetrahydrofuran-3-yl) -2-(4-oxo-8-(pyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-3(4H)-yl ) propanamide (clxxix) 3-(2-hydroxy-2-methylpropyl)-8-(1H-pyrazol-4-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido [3 ,4-d]pyrimidin-4(3H)-one (clxxx)(S)-6-(4-chlorophenyl)-3-(1-hydroxypropan-2-yl)-8-(1H-pyrazole-1- yl)pyrido[3,4-d]pyrimidin-4(3H)-one (clxxxi)(S)-3-(1-hydroxypropan-2-yl)-8-(1H-pyrazol-1-yl)- 6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (clxxxii)3-((3S,4R)-4-hydroxytetrahydrofuran-3 -yl)-8-(pyridin-3-yl)-6-(2-(trifluoromethyl)thiazol-5-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (clxxxiii)3 -(2-hydroxy-2-methylpro Pyr)-8-(1-methyl-1H-pyrazol-4-yl)-6-(2-(trifluoromethyl)thiazol-5-yl)pyrido[3,4-d]pyrimidine-4(3H)- On (clxxxiv) 3-((3S,4R)-4-hydroxytetrahydrofuran-3-yl)-8-(1-methyl-1H-pyrazol-4-yl)-6-(2-(trifluoromethyl)thiazole -5-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (clxxxv)3-((3R,4S)-4-hydroxytetrahydrofuran-3-yl)-8-(1-methyl- 1H-pyrazol-4-yl)-6-(2-(trifluoromethyl)thiazol-5-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (clxxxvi)3-((3R, 4S)-4-hydroxytetrahydrofuran-3-yl)-8-(pyridin-3-yl)-6-(2-(trifluoromethyl)thiazol-5-yl)pyrido[3,4-d]pyrimidine-4 (3H)-one (clxxxvii) (S)-3-(1-hydroxypropan-2-yl)-8-morpholino-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4 -d]pyrimidin-4(3H)-one (clxxxviii) 3-(2-hydroxy-2-methylpropyl)-8-(piperidin-1-yl)-6-(6-(trifluoromethyl)pyridine-3 -yl)pyrido[3,4-d]pyrimidin-4(3H)-one (clxxxix)(S)-3-(1-hydroxypropan-2-yl)-6-(5-methylpyridin-2-yl )-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxc)(S)-3-(1-hydroxypropan-2-yl)-6-( 5-methylpyrimidin-2-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxci)(S)-8-(cyclohex-1-ene -1-yl)-3-(1-hydroxypropan-2-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidine-4(3H)- On(cxcii)(S)-8-cyclohexyl-3-(1-hydroxypropan-2-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidine -4(3H)-on(cxciii)(S)-3-(1 -hydroxypropan-2-yl)-N,N-dimethyl-4-oxo-8-(pyridin-3-yl)-3,4-dihydropyrido[3,4-d]pyrimidine-6-carboxamide (cxciv) ( S)-3-(1-hydroxypropan-2-yl)-8-(1H-pyrazol-4-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4- d] pyrimidin-4(3H)-one (cxcv) (S)-3-(1-hydroxypropan-2-yl)-6-(2-methoxyethyl)-8-(pyridin-3-yl)pyrido [ 3,4-d]pyrimidin-4(3H)-one (cxcvi)(S)-3-(1-hydroxypropan-2-yl)-8-(2-methoxyethyl)-6-(5-(tri Fluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one.

The compounds of Formula I or Formula Ia and their pharmaceutically acceptable salts can be incorporated into pharmaceutical compositions. In some embodiments, the present disclosure relates to pharmaceutical compositions comprising at least one entity selected from compounds of Formula I or Formula Ia and pharmaceutically acceptable salts thereof. In some embodiments, the present disclosure relates to pharmaceutical compositions consisting essentially of at least one entity selected from compounds of Formula I or Formula Ia and pharmaceutically acceptable salts thereof.

In some embodiments, at least one entity selected from compounds of Formula I or Formula Ia and pharmaceutically acceptable salts thereof can be administered in combination with at least one additional therapy. In some embodiments, the at least one additional therapy is selected from immune checkpoint inhibitors (ICIs).

In some embodiments, the at least one additional therapy is selected from anti-CTLA-4 compounds, anti-PD-1 compounds, and anti-PDL-1 compounds. In some embodiments, the at least one additional therapy is pembrolizumab (Keytruda); nivolumab (Opdivo); ipilimumab (Yervoy); avelumab (Bavencio); tripalizumab (Tuoyi); camrelizumab (AiRuiKa); spartalizumab; and tislelizumab. In some embodiments, the at least one additional therapy is an anti-LAG-3 (lymphocyte activation gene-3) compound; an anti-TIM-3 (T cell immunoglobulin and mucin domain containing-3) compound; an anti-TIGIT (T cell immunoglobulin and ITIM domain) compounds; anti-VISTA (V domain Ig suppressor of T cell activation) compounds; or combinations thereof. Non-limiting examples of anti-LAG-3 compounds include IMP321 (eftiragimod alfa), relatolimab (BMS-986016), LAG525, MK-4280, REGN3767, TSR-033, BI754111, Sym022, FS118, and MGD013 There is Non-limiting examples of anti-TIM-3 compounds include TSR-022, MBG453, Sym023, INCAGN2390, LY3321367, BMS-986258, SHR-1702, RO7121661. Non-limiting examples of anti-TIGIT compounds include MK-7684, etigilimab (OMP-313), tiragolumab (MTIG7192A, RG-6058), BMS-986207, AB-154, and ASP-8374. Non-limiting examples of anti-VISTA compounds include JNJ-61610588 and CA-170.

In some embodiments, the pharmaceutical composition comprises at least one entity selected from compounds of Formula I or Formula Ia and pharmaceutically acceptable salts thereof and at least one pharmaceutically acceptable excipient including. Pharmaceutically acceptable excipients are well known to those of ordinary skill in the art and, by way of non-limiting example, see Remington: The Science and Practice of Pharmacy, 22nd Edition, Lippincott Williams & Wilkins, Philadelphia, Pa., incorporated herein by reference. (2013) and all other editions. In some embodiments, the pharmaceutical composition further comprises at least one at least one additional therapy.

optionally at least one A pharmaceutical composition further comprising at least one at least one additional therapy can be used for therapeutic treatment.

The compounds, pharmaceutically acceptable salts, additional therapies, and/or pharmaceutical compositions can be administered to mammalian subjects, including humans, in unit dosage forms. Suitable non-limiting examples of dosage unit forms include forms to be administered orally and forms to be administered by parenteral/systemic routes, non-limiting examples of which are inhalation, subcutaneous administration, intramuscular administration. , intravenous administration, intradermal administration, and intravitreal administration.

In some embodiments, pharmaceutical compositions suitable for oral administration can be in the form of tablets, pills, powders, hard gelatin capsules, soft gelatin capsules, and/or granules. In some embodiments of such pharmaceutical compositions, a compound of the disclosure and/or a pharmaceutically acceptable salt of a compound of the disclosure is admixed with one or more inert diluents, which Non-limiting examples include starch, cellulose, sucrose, lactose, and silica. In some embodiments, such pharmaceutical compositions may further comprise one or more substances other than diluents such as (as non-limiting examples) lubricants, colorants, coatings, or varnishes. In some embodiments, such pharmaceutical compositions may further comprise at least one at least one additional therapy.

In some embodiments, pharmaceutical compositions for parenteral administration can be in the form of aqueous solutions, non-aqueous solutions, suspensions, emulsions, drops, or any combination thereof. In some embodiments, such pharmaceutical compositions comprise one of water, pharmaceutically acceptable glycols, pharmaceutically acceptable oils, pharmaceutically acceptable organic esters, or other pharmaceutically acceptable solvents. It may contain more than seeds. In some embodiments, such pharmaceutical compositions may further comprise at least one at least one additional therapy.

In some embodiments, a method of inhibiting AhR, comprising administering to a subject in need thereof at least one entity selected from compounds of Formula I or Formula Ia and pharmaceutically acceptable salts thereof. Disclosed herein are methods that include administering. In some embodiments, a method of decreasing AhR activity comprises administering to a subject in need thereof at least one entity selected from compounds of Formula I or Formula Ia and pharmaceutically acceptable salts thereof. Disclosed herein are methods comprising administering a tea. In some embodiments, such pharmaceutical compositions may further comprise at least one at least one additional therapy.

In some embodiments, a method of treating cancer, comprising administering to a subject in need thereof at least one entity selected from compounds of Formula I or Formula Ia and pharmaceutically acceptable salts thereof. Disclosed herein are methods that include administering. In some embodiments, the cancer is selected from liquid tumors and solid tumors. In some embodiments, the cancer is breast cancer, respiratory tract cancer, brain cancer, genital cancer, gastrointestinal cancer, urinary tract cancer, eye cancer, liver cancer, skin cancer, head and neck cancer, thyroid cancer, parathyroid cancer , and any of the transitions described above. In some embodiments, the cancer is selected from breast cancer, pancreatic cancer, prostate cancer, and colon cancer. In some embodiments, the cancer is selected from lymphoma, sarcoma, and leukemia.

In some embodiments, a method of treating cancer, comprising administering to a subject in need thereof at least one entity selected from compounds of Formula I or Formula Ia and pharmaceutically acceptable salts thereof; Methods disclosed herein include administering at least one additional therapy. In some embodiments, the cancer is non-small cell lung cancer (NSCLC); small cell lung cancer; head and neck squamous cell carcinoma; renal cell carcinoma; gastric adenocarcinoma; pleural mesothelioma; triple-negative breast cancer (TNBC); esophageal neoplasm; multiple myeloma; gastric and esophagogastric junction cancer; melanoma; esophagogastric junction cancer; metastatic melanoma; metastatic non-cutaneous melanoma; urothelial carcinoma; Cellular lymphoma; renal cell carcinoma; ovarian cancer, fallopian tube cancer; peritoneal neoplasm; extensive-stage small cell lung cancer; bladder cancer; transitional cell carcinoma; Squamous cell carcinoma (SCCHN); recurrent squamous lung cancer; advanced solid malignancies; SCCHN; hypopharyngeal squamous cell carcinoma; laryngeal squamous cell carcinoma; , pancreatic cancer, glioblastoma, metastatic cancer, prostate cancer, solid organ cancer; gastric cancer; colon cancer; and liver cancer.

In some embodiments, a method of treating an ocular disease, comprising administering to a subject in need thereof at least one entity selected from compounds of Formula I or Formula Ia and pharmaceutically acceptable salts thereof. and optionally administering at least one additional therapy are disclosed herein.

For the methods disclosed herein, the mode (or modes) of administration, dosage (or doses), and dosage form (or dosage forms) may include, as non-limiting examples, the compound and/or potency of a pharmaceutically acceptable salt of the compound, at least one additional therapy (if any), age of the patient, weight of the patient, severity of the condition (or conditions) in the patient, patient to treatment tolerability of the drug, as well as secondary effects observed during treatment, can be determined according to criteria generally considered during the establishment of patient treatment. Determination of dosages effective to provide therapeutic benefit for a particular mode and frequency of administration is well within the capabilities of those skilled in the art.

In some embodiments, the compound of Formula I or Formula Ia and/or pharmaceutically acceptable salt thereof is present in the pharmaceutical composition in an amount ranging from 5 μg to 2,000 mg. In some embodiments, a compound of this disclosure and/or a pharmaceutically acceptable salt thereof is present in the pharmaceutical composition in an amount ranging from 5 μg to 1,000 mg. In some embodiments, a compound of this disclosure and/or a pharmaceutically acceptable salt thereof is present in the pharmaceutical composition in an amount ranging from 5 μg to 500 mg. In some embodiments, a compound of this disclosure and/or a pharmaceutically acceptable salt thereof is present in the pharmaceutical composition in an amount ranging from 5 μg to 250 mg. In some embodiments, a compound of this disclosure and/or a pharmaceutically acceptable salt thereof is present in the pharmaceutical composition in an amount ranging from 5 μg to 100 mg. In some embodiments, a compound of this disclosure and/or a pharmaceutically acceptable salt thereof is present in the pharmaceutical composition in an amount ranging from 5 μg to 50 mg.

In some embodiments, a compound of this disclosure and/or a pharmaceutically acceptable salt thereof is present in the pharmaceutical composition in an amount ranging from 1 mg to 5,000 mg. In some embodiments, a compound of this disclosure and/or a pharmaceutically acceptable salt thereof is present in the pharmaceutical composition in an amount ranging from 1 mg to 3,000 mg. In some embodiments, a compound of this disclosure and/or a pharmaceutically acceptable salt thereof is present in the pharmaceutical composition in an amount ranging from 1 mg to 2,000 mg. In some embodiments, a compound of this disclosure and/or a pharmaceutically acceptable salt thereof is present in the pharmaceutical composition in an amount ranging from 1 mg to 1,000 mg. In some embodiments, a compound of this disclosure and/or a pharmaceutically acceptable salt thereof is present in the pharmaceutical composition in an amount ranging from 1 mg to 500 mg. In some embodiments, a compound of this disclosure and/or a pharmaceutically acceptable salt thereof is present in the pharmaceutical composition in an amount ranging from 1 mg to 250 mg. In some embodiments, a compound of this disclosure and/or a pharmaceutically acceptable salt thereof is present in the pharmaceutical composition in an amount ranging from 1 mg to 100 mg. In some embodiments, a compound of this disclosure and/or a pharmaceutically acceptable salt thereof is present in the pharmaceutical composition in an amount ranging from 1 mg to 50 mg.

In some embodiments, a compound of the disclosure and/or a pharmaceutically acceptable salt thereof is in the pharmaceutical composition at 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg , 40mg, 45mg, 50mg, 60mg, 70mg, 80mg, 90mg, 100mg, 125mg, 150mg, 175mg, 200mg, 225mg, 250mg, 300mg, 350mg, 400mg, 450mg, 500mg, 550mg, 600mg, 650mg, 700mg, 750mg, 800mg , 850 mg, 900 mg, 1,000 mg, 1,100 mg, 1,200 mg, 1,300 mg, 1,400 mg, 1,500 mg, 1,600 mg, 1,700 mg, 1,800 mg, 1,900 mg, 2,000 mg, 2 , 100mg, 2,200mg, 2,300mg, 2,400mg, 2,500mg, 2,600mg, 2,700mg, 2,800mg, 2,900mg, 3,000mg, 3,100mg, 3,200mg, 3,300mg , 3,400 mg, 3,500 mg, 3,600 mg, 3,700 mg, 3,800 mg, 3,900 mg, 4,000 mg, 4,100 mg, 4,200 mg, 4,300 mg, 4,400 mg, 4,500 mg, 4 , 600 mg, 4,700 mg, 4,800 mg, 4,900 mg, or 5,000 mg.

Effective amounts and doses can be estimated initially from in vitro assays. For example, an initial dose for use in animals can be formulated to achieve a circulating blood or serum concentration of the active compound that is greater than or equal to the _IC50 for the particular compound as determined in in vitro assays. Calculating dosages to achieve such circulating blood or serum concentrations taking into account the bioavailability of the particular compound is well within the capabilities of those skilled in the art. For guidance, the reader is referred to Goodman and Gilman's The Pharmaceutical Basis of Therapeutics, Chapter 1, pp. 1-46, latest edition, Fingl & Woodbury, in Pergamagon Press, "General Principles" and references cited therein, the methods of which are hereby incorporated by reference in their entirety. Initial doses can also be estimated from in vivo data, such as animal models. Animal models useful for testing the efficacy of compounds to treat or prevent various diseases described in this disclosure are well known in the art.

In some embodiments, the dosage administered ranges from 0.0001 or 0.001 or 0.01 mg/kg/day to 100 mg/kg/day, but the activity of the compound, among other factors, , may be higher or lower depending on its bioavailability, mode of administration, and various factors discussed above. Dosage amount and interval can be adjusted individually to provide plasma levels of the compounds that are sufficient to maintain therapeutic or prophylactic effect. For example, the compound may be administered once weekly, several times weekly (e.g., every other day), once daily, depending on, among other things, the mode of administration, the specific indication being treated, and the judgment of the prescribing physician. , or multiple doses per day. In cases of local administration or selective uptake, such as topical administration, the effective local concentration of active compound may not be related to plasma concentration. Those skilled in the art will be able to optimize effective topical doses without undue experimentation.

及びその薬学的に許容できる塩
（式中：
Ｒ^１及びＲ^２のそれぞれは、任意選択で置換されたアルキル、任意選択で置換されたエステル、任意選択で置換されたヘテロアルキル、任意選択で置換されたアシル、任意選択で置換されたアミド、任意選択で置換されたアリール、任意選択で置換されたヘテロアリール、任意選択で置換されたシクロアルキル、任意選択で置換されたアミン、及び任意選択で置換されたヘテロシクロアルキルから独立に選択され；且つ
Ｒ^３は、水素、任意選択で置換されたアルキル、任意選択で置換されたアシル、任意選択で置換されたアミド、任意選択で置換されたアリール、任意選択で置換されたシクロアルキル、任意選択で置換されたエステル、任意選択で置換されたヘテロアルキル、任意選択で置換されたヘテロアリール、任意選択で置換されたヘテロシクロアルキル、任意選択で置換されたアミン、シアノ、ハロ、ヒドロキシ、及び－Ｃ（Ｏ）Ｈから選択される）。 Non-limiting embodiments of the present disclosure include:
1. Compounds of Formula I:

and a pharmaceutically acceptable salt thereof (wherein:
each of R ¹ and R ² is optionally substituted alkyl, optionally substituted ester, optionally substituted heteroalkyl, optionally substituted acyl, optionally substituted amide, independently selected from optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted amine, and optionally substituted heterocycloalkyl; and R ³ is hydrogen, optionally substituted alkyl, optionally substituted acyl, optionally substituted amido, optionally substituted aryl, optionally substituted cycloalkyl, optionally optionally substituted heteroalkyl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, optionally substituted amine, cyano, halo, hydroxy, and — C(O)H).

又はその薬学的に許容できる塩
（式中：
環Ａは、任意選択で置換されたアリール、任意選択で置換されたヘテロアリール、任意選択で置換されたシクロアルキル、及び任意選択で置換されたヘテロシクロアルキルから選択され；
環Ｂは、任意選択で置換されたアリール、任意選択で置換されたヘテロアリール、任意選択で置換されたシクロアルキル、及び任意選択で置換されたヘテロシクロアルキルから選択され；且つ
Ｒは、水素、任意選択で置換されたアルキル、任意選択で置換されたアシル、任意選択で置換されたアミド、任意選択で置換されたアリール、任意選択で置換されたシクロアルキル、任意選択で置換されたエステル、任意選択で置換されたヘテロアルキル、任意選択で置換されたヘテロアリール、任意選択で置換されたヘテロシクロアルキル、アミノ、シアノ、ハロ、ヒドロキシ、及び－Ｃ（Ｏ）Ｈから選択される）。 2. Compounds of Formula Ia

or a pharmaceutically acceptable salt thereof (wherein:
Ring A is selected from optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, and optionally substituted heterocycloalkyl;
Ring B is selected from optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, and optionally substituted heterocycloalkyl; and R is hydrogen; optionally substituted alkyl, optionally substituted acyl, optionally substituted amide, optionally substituted aryl, optionally substituted cycloalkyl, optionally substituted ester, optional optionally substituted heteroalkyl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, amino, cyano, halo, hydroxy, and -C(O)H).

3. Ring A is optionally substituted 6-10 membered aryl, optionally substituted 5-10 membered heteroaryl, optionally substituted 3-10 membered cycloalkyl, and optionally substituted 3 is selected from -10 membered heterocycloalkyl;
Ring B is optionally substituted 6-10 membered aryl, optionally substituted 5-10 membered heteroaryl, optionally substituted 3-10 membered cycloalkyl, and optionally substituted 3 is selected from -10 membered heterocycloalkyl;
R is hydrogen, optionally substituted C ₁ -C ₁₀ alkyl, optionally substituted 6-10 membered aryl, —C(O)R′, —C(O)NR′R′, optionally 3-10 membered cycloalkyl substituted with, —C(O)OR′, optionally substituted C ₁ -C ₁₀ heteroalkyl, optionally substituted 5-10 membered heteroaryl, optionally substituted 3-10 membered heterocycloalkyl, amino, cyano, halo, hydroxy, and —C(O)H; and each R′ is hydrogen, optionally substituted C ₁ -C ₁₀ alkyl, A compound of Embodiment 2, or a pharmaceutically acceptable salt thereof, independently selected from C ₁ -C ₁₀ heteroalkyl and optionally substituted C 1 -C 10 heteroalkyl.

4. Ring A is selected from 6-10 membered aryl, 5-10 membered heteroaryl, 3-10 membered cycloalkyl, and 3-10 membered heterocycloalkyl, wherein each 6-10 membered aryl, 5-10 membered heteroaryl, 3-10 membered cycloalkyl, and 3-10 membered heterocycloalkyl are optionally substituted independently with 1-5 instances of R ^A ;
Ring B is selected from 6-10 membered aryl, 5-10 membered heteroaryl, 3-10 membered cycloalkyl, and 3-10 membered heterocycloalkyl, wherein each 6-10 membered aryl, 5-10 membered heteroaryl, 3-10 membered cycloalkyl, and 3-10 membered heterocycloalkyl are optionally substituted independently with 1-5 instances of R ^B ;
R is hydrogen, C ₁ -C ₁₀ alkyl, 6-10 membered aryl, —C(O)R′, —C(O)NR′R′, 3-10 membered cycloalkyl, —C(O)OR′ , C ₁ -C ₁₀ heteroalkyl, 5-10 membered heteroaryl, 3-10 membered heterocycloalkyl, amino, cyano, halo, hydroxy, and —C(O)H, wherein each C ₁ - C ₁₀ alkyl, 6-10 membered aryl, 3-10 membered cycloalkyl, C ₁ -C ₁₀ heteroalkyl, 5-10 membered heteroaryl, and 3-10 membered heterocycloalkyl are represented by 1-5 examples of ^R independently optionally substituted;
each R′ is independently selected from hydrogen, C ₁ -C ₁₀ alkyl, C ₁ -C ₁₀ haloalkyl, C ₁ -C ₁₀ hydroxyalkyl, and C ₁ -C ₁₀ heteroalkyl;
Each R ^A is halo, hydroxy, C ₁ -C ₁₀ alkyl, C ₁ -C ₁₀ haloalkyl, C ₁ -C ₁₀ alkoxy, C ₁ -C ₁₀ haloalkoxy, C ₁ -C ₁₀ hydroxyalkyl, and NR″ independently selected from R'';
Each R ^B is halo, hydroxy, C ₁ -C ₁₀ alkyl, C ₁ -C ₁₀ haloalkyl, C ₁ -C ₁₀ alkoxy, C ₁ -C ₁₀ haloalkoxy, C ₁ -C ₁₀ hydroxyalkyl, and NR″ independently selected from R'';
Each R ^C is halo, hydroxy, cyano, C ₁ -C ₁₀ alkyl, C ₁ -C ₁₀ alkoxy, C ₁ -C ₁₀ haloalkyl, 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, 6-10 independently selected from 5- to 10-membered heteroaryl; and each R″ is hydrogen, C ₁ -C ₁₀ alkyl, C ₁ -C ₁₀ haloalkyl, C ₁ -C ₁₀ hydroxyalkyl, and C ₁ A compound of Embodiment 2 or 3, or a pharmaceutically acceptable salt thereof, independently selected from _{-C10heteroalkyl} .

5. A compound of Embodiment 4, or a pharmaceutically acceptable salt thereof, wherein Ring A is selected from 3-10 membered cycloalkyl optionally substituted with 1-5 instances of R 1 ^A.

6. ^A compound of embodiment 4 or 5, or the pharmaceutically acceptable salt.

7. A compound of Embodiment 4, or a pharmaceutically acceptable salt thereof, wherein Ring A is selected from 6-8 membered aryl optionally substituted with 1-5 instances of R 1 ^A.

8. A compound of Embodiment 4 or 7, or a pharmaceutically acceptable salt thereof, wherein Ring ^A is phenyl optionally substituted with 1-3 instances of RA.

9. A compound of Embodiment 4, or a pharmaceutically acceptable salt thereof, wherein Ring A is selected from 5-8 membered heteroaryl optionally substituted with 1-5 instances of R 1 ^A.

10. Ring A is selected from pyrrolyl, furanyl, furazanyl, thiophenyl, imidazolyl, isothiazolyl, isoxazolyl, oxazolyl, oxadiazolyl, tetrazolyl, thiazolyl, triazolyl, pyrazolyl, pyridinyl, pyrazinyl, pyridazinyl, and pyrimidinyl;
wherein pyrrolyl, furanyl, furazanyl, thiophenyl, imidazolyl, isothiazolyl, isoxazolyl, oxazolyl, oxadiazolyl, tetrazolyl, thiazolyl, triazolyl, pyrazolyl, pyridinyl, pyrazinyl, pyridazinyl, and pyrimidinyl are each independently represented by 1 to 3 instances of R ^A A compound of Embodiment 4 or 9, or a pharmaceutically acceptable salt thereof, optionally substituted with .

11. The compound of any one of Embodiments 4, 9, or 10, or a pharmaceutically acceptable salt thereof, wherein Ring ^A is pyridinyl optionally substituted with 1-3 instances of RA.

12. A compound of Embodiment 4, or a pharmaceutically acceptable salt thereof, wherein Ring A is selected from 5-8 membered heterocycloalkyl optionally substituted with 1-5 instances of R 1 ^A.

13. Ring A is selected from pyrrolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, morpholino, azepinyl, tetrahydropyranyl, and tetrahydrofuranyl;
wherein each of pyrrolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, morpholino, azepinyl, tetrahydropyranyl, and tetrahydrofuranyl is independently optionally substituted with 1-3 instances of ^RA . A compound or a pharmaceutically acceptable salt thereof.

14. The compound of any one of Embodiments 4, 12, or 13, or a pharmaceutically acceptable salt thereof, wherein Ring ^A is piperidinyl or morpholino optionally substituted with 1-3 instances of RA.

15. A compound of Embodiment 4, or a pharmaceutically acceptable salt thereof, wherein ring B is selected from 6-8 membered aryl optionally substituted with 1-5 instances of R 1 ^B.

16. A compound of Embodiment 4 or 15, or a pharmaceutically acceptable salt thereof, wherein Ring B is phenyl optionally substituted with 1-3 instances of R 1 ^B.

17. A compound of Embodiment 4, or a pharmaceutically acceptable salt thereof, wherein Ring B is selected from benzodioxolyl and 5-8 membered heteroaryl optionally substituted with 1-5 instances of R 1 ^B.

18. Ring B is selected from benzodioxolyl, pyrrolyl, furanyl, furazanyl, thiophenyl, imidazolyl, isothiazolyl, isoxazolyl, oxazolyl, oxadiazolyl, tetrazolyl, thiazolyl, triazolyl, pyrazolyl, pyridinyl, pyrazinyl, pyridazinyl, pyridinonyl, and pyrimidinyl;
wherein each of benzodioxolyl, pyrrolyl, furanyl, furazanyl, thiophenyl, imidazolyl, isothiazolyl, isoxazolyl, oxazolyl, oxadiazolyl, tetrazolyl, thiazolyl, triazolyl, pyrazolyl, pyridinyl, pyrazinyl, pyridazinyl, and pyrimidinyl is represented by 1 to 3 examples; or a pharmaceutically ^acceptable salt thereof.

19. Ring B is selected from pyrazolyl, isothiazolyl, isoxazolyl, pyridinyl, pyrimidinyl, and thiophenyl;
wherein each of pyrazolyl, isothiazolyl, isoxazolyl, pyridinyl, pyrimidinyl, and thiophenyl is independently optionally substituted with 1-3 instances of R ^B . A compound or a pharmaceutically acceptable salt thereof.

20. each R ^A is independently selected from halo, C ₁ -C ₁₀ alkyl, C ₁ -C ₁₀ haloalkyl, C ₁ -C ₁₀ alkoxy, C ₁ -C ₁₀ haloalkoxy, and NR″R″;
each R ^B is independently selected from halo, C ₁ -C ₁₀ alkyl, and C ₁ -C ₁₀ haloalkyl;
each R ^C is independently selected from halo, hydroxy, cyano, C ₁ -C ₁₀ alkyl, C ₁ -C ₁₀ alkoxy, 3-8 membered cycloalkyl, 3-8 membered heterocycloalkyl, and 6-8 membered aryl and each R″ is independently selected from hydrogen and C ₁ -C ₁₀ alkyl, or a pharmaceutically acceptable salt thereof.

から選択される、実施形態２～４及び７～２０のいずれか１つの化合物又はその薬学的に許容できる塩。 21. Ring A is

A compound of any one of embodiments 2-4 and 7-20, or a pharmaceutically acceptable salt thereof, selected from:

から選択される、実施形態２～６及び１５～２０のいずれか１つの化合物又はその薬学的に許容できる塩。 22. Ring A is

A compound of any one of embodiments 2-6 and 15-20, or a pharmaceutically acceptable salt thereof, selected from:

から選択される、実施形態２～４及び７～２０のいずれか１つの化合物又はその薬学的に許容できる塩。 23. Ring A is

A compound of any one of embodiments 2-4 and 7-20, or a pharmaceutically acceptable salt thereof, selected from:

から選択される、実施形態２～４及び７～２０のいずれか１つの化合物又はその薬学的に許容できる塩。 24. Ring B is

A compound of any one of embodiments 2-4 and 7-20, or a pharmaceutically acceptable salt thereof, selected from:

から選択される、実施形態２～１４及び２０のいずれか１つの化合物又はその薬学的に許容できる塩。 25. Ring B is

A compound of any one of embodiments 2-14 and 20, or a pharmaceutically acceptable salt thereof, selected from:

から選択される、実施形態２～４及び７～２０のいずれか１つの化合物又はその薬学的に許容できる塩。 26. Ring B is

A compound of any one of embodiments 2-4 and 7-20, or a pharmaceutically acceptable salt thereof, selected from:

から選択される、実施形態２～２６のいずれか１つの化合物又はその薬学的に許容できる塩。 27. R is methyl;

A compound of any one of embodiments 2-26, or a pharmaceutically acceptable salt thereof, selected from:

から選択される、実施形態２～２７のいずれか１つの化合物又はその薬学的に許容できる塩。 28. R is methyl;

A compound of any one of embodiments 2-27, or a pharmaceutically acceptable salt thereof, selected from:

29. At least one entity selected from the following compounds and pharmaceutically acceptable salts thereof:
(i) (S)-8-(5-fluoropyridin-3-yl)-3-(1-hydroxypropan-2-yl)-6-(4-(trifluoromethoxy)phenyl)pyrido[3,4 -d]pyrimidin-4(3H)-one;
(ii) (S)-6-(4-chlorophenyl)-3-(1-hydroxypropan-2-yl)-8-(6-oxo-1,6-dihydropyridin-3-yl)pyrido[3,4 -d]pyrimidin-4(3H)-one;
(iii) (S)-8-(benzo[d][1,3]dioxol-4-yl)-6-(4-chlorophenyl)-3-(1-hydroxypropan-2-yl)pyrido[3, 4-d]pyrimidin-4(3H)-one;
(iv) (S)-3-(1-hydroxypropan-2-yl)-8-(pyridin-4-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido [3, 4-d]pyrimidin-4(3H)-one;
(v) (S)-8-(5-fluoropyridin-3-yl)-3-(1-hydroxypropan-2-yl)-6-(4-(trifluoromethyl)phenyl)pyrido[3,4 -d]pyrimidin-4(3H)-one;
(vi) (S)-3-(1-hydroxypropan-2-yl)-6,8-di(pyridin-4-yl)pyrido[3,4-d]pyrimidin-4(3H)-one;
(vii) (S)-6-(4-chlorophenyl)-8-(3-fluorophenyl)-3-(1-hydroxypropan-2-yl)pyrido[3,4-d]pyrimidine-4(3H) -on;
(viii) (S)-8-(3-fluorophenyl)-3-(1-hydroxypropan-2-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4 -d]pyrimidin-4(3H)-one;
(ix) 3-(2-hydroxy-2-methylpropyl)-8-(pyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d] pyrimidin-4(3H)-one;
(x) 6,8-di(pyridin-3-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)pyrido[3,4-d]pyrimidin-4(3H)-one;
(xi) (S)-6-chloro-3-(1-hydroxypropan-2-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one;
(xii) (S)-3-(1-hydroxypropan-2-yl)-8-(pyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido [3, 4-d]pyrimidin-4(3H)-one;
(xiii) 6-(4-chlorophenyl)-8-(pyridin-3-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)pyrido[3,4-d]pyrimidine-4 ( 3H)—on;
(xiv) 8-(pyridin-3-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)-6-(4-(trifluoromethoxy)phenyl)pyrido[3,4-d ] pyrimidin-4(3H)-one;
(xv) 6-(4-chlorophenyl)-8-(1-methyl-1H-pyrazol-4-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)pyrido[3,4- d] pyrimidin-4(3H)-one;
(xvi) 3-(2-hydroxy-2-methylpropyl)-8-(pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyrimidine-4 ( 3H)—on;
(xvii) (S)-3-(1-hydroxypropan-2-yl)-8-(pyridin-3-yl)-6-(p-tolyl)pyrido[3,4-d]pyrimidine-4(3H )-on;
(xviii) 6-(4-chlorophenyl)-3-(2-hydroxy-2-methylpropyl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one;
(xix) 3-(2-hydroxy-2-methylpropyl)-6,8-bis(1-methyl-1H-pyrazol-4-yl)pyrido[3,4-d]pyrimidin-4(3H)-one ;
(xx) (S)-3-(1-hydroxypropan-2-yl)-6,8-di(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one;
(xxi) 6-(4-chlorophenyl)-3-(2-hydroxy-2-methylpropyl)-8-(1-methyl-1H-pyrazol-4-yl)pyrido[3,4-d]pyrimidine-4 (3H)-on;
(xxii) (S)-3-(1-hydroxypropan-2-yl)-8-(pyridin-3-yl)-6-(4-(trifluoromethoxy)phenyl)pyrido[3,4-d] pyrimidin-4(3H)-one;
(xxiii) (S)-3-(1-hydroxypropan-2-yl)-8-(pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrido[3,4-d] pyrimidin-4(3H)-one;
(xxiv) (S)-6-(4-chlorophenyl)-3-(1-hydroxypropan-2-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidine-4(3H )-on;
(xxv) (S)-3-(1-hydroxypropan-2-yl)-8-(1-methyl-1H-pyrazol-4-yl)-6-(4-(trifluoromethoxy)phenyl)pyrido [ 3,4-d]pyrimidin-4(3H)-one;
(xxvi) (S)-3-(1-hydroxypropan-2-yl)-8-(1-methyl-1H-pyrazol-4-yl)-6-phenylpyrido[3,4-d]pyrimidine-4 ( 3H)—on;
(xxvii) (S)-6-(4-chlorophenyl)-3-(1-hydroxypropan-2-yl)-8-(1-methyl-1H-pyrazol-4-yl)pyrido [3,4-d ] pyrimidin-4(3H)-one;
(xxviii) 3-methyl-8-(pyridin-3-yl)-6-(4-(trifluoromethoxy)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one;
(xxix) Rac-6-(4-chlorophenyl)-3-((trans)-4-hydroxytetrahydrofuran-3-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidine-4 (3H)-on;
(xxx) (S)-6-(4-chlorophenyl)-3-(3-hydroxy-3-methylbutan-2-yl)-8-(1-methyl-1H-pyrazol-4-yl)pyrido [3, 4-d]pyrimidin-4(3H)-one;
(xxxi) (R)-6-(4-chlorophenyl)-3-(3-hydroxy-3-methylbutan-2-yl)-8-(1-methyl-1H-pyrazol-4-yl)pyrido [3, 4-d]pyrimidin-4(3H)-one;
(xxxii) rac-6-(4-chlorophenyl)-3-((cis)-4-hydroxytetrahydrofuran-3-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidine-4 (3H)-on;
(xxxiii) (R)-6-(4-chlorophenyl)-3-(3-hydroxy-3-methylbutan-2-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidine- 4(3H)-on;
(xxxiv) (S)-3-(3-hydroxy-3-methylbutan-2-yl)-6,8-di(pyridin-3-yl)pyrido[3,4-d]pyrimidine-4(3H)- on;
(xxxv) (S)-6,8-bis(3,5-difluorophenyl)-3-(1-hydroxy-3-methylbutan-2-yl)pyrido[3,4-d]pyrimidine-4(3H) -on;
(xxxvi) (S)-6-(4-chlorophenyl)-3-(3-hydroxy-3-methylbutan-2-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidine- 4(3H)-on;
(xxxvii) (S)-8-(3,5-difluorophenyl)-3-(1-hydroxy-3-methylbutan-2-yl)-6-(p-tolyl)pyrido[3,4-d]pyrimidine -4(3H)-one;
(xxxviii) 6-(4-chlorophenyl)-8-(3-fluorophenyl)-3-(2-hydroxy-2-methylpropyl)pyrido[3,4-d]pyrimidin-4(3H)-one;
(xxxix) (R)-6-(4-chlorophenyl)-8-(3-fluorophenyl)-3-(3-hydroxy-3-methylbutan-2-yl)pyrido[3,4-d]pyrimidine-4 (3H)-on;
(xl) (S)-3-(1-(benzyloxy)propan-2-yl)-8-(3-fluorophenyl)-6-(p-tolyl)pyrido[3,4-d]pyrimidine-4 (3H)-on;
(xli) (R)-6-(4-chlorophenyl)-8-(3-fluorophenyl)-3-(3,3,3-trifluoro-2-hydroxypropyl)pyrido[3,4-d]pyrimidine -4(3H)-one;
(xlii) (S)-6-(4-chlorophenyl)-8-(3-fluorophenyl)-3-(3,3,3-trifluoro-2-hydroxypropyl)pyrido[3,4-d]pyrimidine -4(3H)-one;
(xliii) (S)-3-(1-hydroxypropan-2-yl)-6-morpholin-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one;
(xliv) (S)-3-(1-hydroxypropan-2-yl)-8-(1H-imidazol-1-yl)-6-(4-(trifluoromethoxy)phenyl)pyrido[3,4- d] pyrimidin-4(3H)-one;
(xlv) (S)-3-(1-methoxypropan-2-yl)-8-(pyridin-3-yl)-6-(p-tolyl)pyrido[3,4-d]pyrimidine-4 (3H )-on;
(xlvi) (S)-3-(1-hydroxypropan-2-yl)-8-(pyridin-3-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido [3, 4-d]pyrimidin-4(3H)-one;
(xlvii) (S)-8-(3-fluorophenyl)-3-(1-hydroxypropan-2-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4 -d]pyrimidin-4(3H)-one;
(xlviii) (S)-8-(3-fluorophenyl)-3-(1-hydroxypropan-2-yl)-6-(p-tolyl)pyrido[3,4-d]pyrimidine-4(3H) -on;
(xlix) (S)-8-(3-fluorophenyl)-3-(1-hydroxypropan-2-yl)-6-(4-(trifluoromethoxy)phenyl)pyrido[3,4-d]pyrimidine -4(3H)-one;
(l) (S)-3-(1-hydroxypropan-2-yl)-8-(pyridin-3-yl)-6-(6-(trifluoromethoxy)pyridin-3-yl)pyrido [3, 4-d]pyrimidin-4(3H)-one (li)(S)-3-(2-hydroxy-2-methylpropyl)-8-(1H-pyrazol-4-yl)-6-(6-( trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (lii)methyl (S)-5-(3-(1-hydroxypropan-2-yl)- 4-oxo-8-(pyridin-3-yl)-3,4-dihydropyrido[3,4-d]pyrimidin-6-yl)picolinate (liii) (S)-3-(1-hydroxypropane-2- yl)-6-(isothiazol-4-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (liv) 3-(2-hydroxy-2 -methylpropyl)-8-(isothiazol-4-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (lv ) (S)-3-(1-hydroxypropan-2-yl)-8-(isothiazol-4-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido [3,4 -d]pyrimidin-4(3H)-one (lvi)(S)-3-(1-hydroxypropan-2-yl)-6,8-di(isothiazol-4-yl)pyrido[3,4- d]pyrimidin-4(3H)-one (lvii)(S)-8-(pyridin-3-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)-6-(6- (trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (lviii) (S)-6-(4-chlorophenyl)-3-(1-hydroxypropane- 2-yl)-8-(isothiazol-4-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (lix) 3-(2-hydroxy-2-methylpropyl)-6,8 -di(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (lx) 3-(2-hydroxy-2-methylpropyl)-8-(1-methyl-1H- pyrazol-4-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (lxi) 6-(4-chloro- 2-methylphenyl)-3-(2-hydroxy-2-methylpropyl)-8-(1-methyl-1H-pyrazol-4-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (lxii) (S)-3-(1-hydroxypropan-2-yl)-8-(1H-pyrazol-4-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido [ 3,4-d]pyrimidin-4(3H)-one (lxiii) (S)-3-(1-hydroxypropan-2-yl)-8-(2-methylpyridin-3-yl)-6-( 6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (lxiv) (S)-3-(1-hydroxypropan-2-yl)-8 -(4-methylpyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (lxv) (S) -3-(1-hydroxypropan-2-yl)-6-(4-methylthiazol-5-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidine-4(3H) -one (lxvi) (S)-6-(2-cyclopropylthiazol-5-yl)-3-(1-hydroxypropan-2-yl)-8-(pyridin-3-yl)pyrido[3,4 -d]pyrimidin-4(3H)-one (lxvii) (S)-3-(1-hydroxypropan-2-yl)-6-(2-isopropylthiazol-5-yl)-8-(pyridin-3 -yl)pyrido[3,4-d]pyrimidin-4(3H)-one (lxviii) (S)-3-(1-hydroxypropan-2-yl)-8-(1-methyl-1H-pyrazole- 4-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (lxix)(S)-3-(1-hydroxy propan-2-yl)-6,8-bis(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (lxx)6-(4- Chlorophenyl)-3-((3S,4S)-4-hydroxytetrahydrofuran-3-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (lxxi) 6-(4-chlorophenyl)-3-((3R,4R)-4-hydroxytetrahydrofuran-3-yl)-8-(pyridin-3-yl) pyrido[3,4-d]pyrimidin-4(3H)-one (lxxii) 3-(2-hydroxyethyl)-8-(pyridin-3-yl)-6-(4-(trifluoromethoxy)phenyl) pyrido[3,4-d]pyrimidin-4(3H)-one (lxxiii)(S)-6-(4-chlorophenyl)-3-(1-hydroxypropan-2-yl)-8-(1-methyl -6-oxo-1,6-dihydropyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (lxxiv)(S)-6-(6-cyclopropylpyridin-3-yl )-3-(1-hydroxypropan-2-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (lxxv)(S)-3-( 1-hydroxypropan-2-yl)-6-(4-methyl-6-(trifluoromethyl)pyridin-3-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidine- 4(3H)-one (lxxvi)(S)-3-(1-hydroxypropan-2-yl)-8-(1-methyl-1H-pyrazol-4-yl)-6-(pyridin-3-yl ) pyrido[3,4-d]pyrimidin-4(3H)-one (lxxvii) (S)-6-(cyclohex-1-en-1-yl)-3-(1-hydroxypropan-2-yl) -8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (lxxviii)(S)-6,8-bis(5-fluoropyridin-3-yl)-3 -(1-hydroxypropan-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (lxxix)3-((3R,4S)-4-hydroxytetrahydrofuran-3-yl)-8 -(pyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (lxxx)3-(2-hydroxy -2-methylpropyl)-8-(pyridin-3-yl)-6-(2-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one ( lxxxi) 6-(6-cyclopropylpyridin-3-yl)-3-(2-hydroxy-2-methylpropyl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidine-4 ( 3H)-one (lxxxii) 6-(6-cyclopropylpyridin-3-yl)-3-(2-hydroxy-2-methyl propyl)-8-(1-methyl-1H-pyrazol-4-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (lxxxiii)(S)-6-(6-cyclopropylpyridine- 3-yl)-3-(1-hydroxypropan-2-yl)-8-(1-methyl-1H-pyrazol-4-yl)pyrido[3,4-d]pyrimidin-4(3H)-one ( lxxxiv) (S)-3-(1-hydroxypropan-2-yl)-8-(pyridin-3-yl)-6-(thiazol-5-yl)pyrido[3,4-d]pyrimidine-4 ( 3H)-one (lxxxv)(S)-3-(1-hydroxypropan-2-yl)-8-(pyridin-3-yl)-6-(2-(trifluoromethyl)thiazol-5-yl) pyrido[3,4-d]pyrimidin-4(3H)-one (lxxxvi)(S)-3-(1-hydroxypropan-2-yl)-8-(pyridin-3-yl)-6-(2 -(trifluoromethyl)pyrimidin-5-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (lxxxvii) 3-(2-hydroxy-2-methylpropyl)-8-(pyridine-3 -yl)-6-(2-(trifluoromethyl)thiazol-5-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (lxxxviii)3-((3S,4S)-4- Hydroxytetrahydrofuran-3-yl)-8-(1-methyl-1H-pyrazol-4-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidine- 4(3H)-one (lxxxix)(S)-3-(1-hydroxypropan-2-yl)-6-(2-methylthiazol-5-yl)-8-(pyridin-3-yl)pyrido [ 3,4-d]pyrimidin-4(3H)-one (xc)(S)-6-(4-chlorophenyl)-8-(3-fluorophenyl)-3-(1-hydroxy-3-methylbutane-2 -yl)pyrido[3,4-d]pyrimidin-4(3H)-one (xci)(S)-3-(1-hydroxypropan-2-yl)-6-(piperidin-1-yl)-8 -(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (xcii) 3-(2-hydroxy-2-methylpropyl)-8-(isothiazol-4-yl) -6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidine-4(3 H)-one (xciii) (S)-3-(1-hydroxypropan-2-yl)-8-(isothiazol-4-yl)-6-(5-(trifluoromethyl)pyridin-2-yl ) pyrido[3,4-d]pyrimidin-4(3H)-one (xciv) 3-(2-hydroxy-2-methylpropyl)-8-(1-methyl-1H-pyrazol-4-yl)-6 -(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (xcv)(S)-8-(pyridin-3-yl)-3- (3,3,3-trifluoro-2-hydroxypropyl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (xcvi ) (3-(2-hydroxy-2-methylpropyl)-8-(pyridin-3-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidine -4(3H)-one (xcvii) 3-(1,1-dioxidotetrahydrothiophen-3-yl)-8-(pyridin-3-yl)-6-(6-(trifluoromethyl)pyridine-3 -yl)pyrido[3,4-d]pyrimidin-4(3H)-one (xcviii) (R)-3-(1,1-dioxidotetrahydrothiophen-3-yl)-8-(pyridin-3- yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (xcix) (R)-3-(2-hydroxypropyl) -8-(1-methyl-1H-pyrazol-4-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one ( c) (S)-3-(2-hydroxypropyl)-8-(1-methyl-1H-pyrazol-4-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido [3 ,4-d]pyrimidin-4(3H)-one (ci)(R)-8-(1-methyl-1H-pyrazol-4-yl)-3-(3,3,3-trifluoro-2- Hydroxypropyl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cii)(S)-8-(1-methyl- 1H-pyrazol-4-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)-6-(6-(trifluoromethyl)pyridine-3 -yl)pyrido[3,4-d]pyrimidin-4(3H)-one (ciii) (R)-3-(2-hydroxypropyl)-8-(pyridin-3-yl)-6-(6- (trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (civ) (R)-8-(1-methyl-1H-pyrazol-4-yl)- 3-(3,3,3-trifluoro-2-hydroxypropyl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cv) 3-((3S,4R)-4-hydroxytetrahydrofuran-3-yl)-8-(1-methyl-1H-pyrazol-4-yl)-6-(6-(trifluoromethyl)pyridine- 3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cvi) 3-((3R,4S)-4-hydroxytetrahydrofuran-3-yl)-8-(1-methyl-1H -pyrazol-4-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cvii)6-(4-chlorophenyl) -3-((3S,4R)-4-hydroxytetrahydrofuran-3-yl)-8-(1-methyl-1H-pyrazol-4-yl)pyrido[3,4-d]pyrimidine-4(3H)- On (cviii) 3-((3S,4R)-4-hydroxytetrahydrofuran-3-yl)-8-(pyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido [3,4-d]pyrimidin-4(3H)-one (cix)(S)-6-(6-cyclopropylpyridin-3-yl)-8-(pyridin-3-yl)-3-(3 ,3,3-trifluoro-2-hydroxypropyl)pyrido[3,4-d]pyrimidin-4(3H)-one (cx)(R)-6-(6-cyclopropylpyridin-3-yl)- 8-(pyridin-3-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxi)(R)- 8-(pyridin-3-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido [3,4- d]pyrimidin-4(3H)-one (cxii) (R)-8-(pyridin-3-yl)-3-(3,3,3-trifluoro-2- Hydroxypropyl)-6-(4-(trifluoromethoxy)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxiii)(S)-8-(pyridin-3-yl)-3 -(3,3,3-trifluoro-2-hydroxypropyl)-6-(4-(trifluoromethoxy)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxiv)6- (4-chlorophenyl)-3-((3S,4R)-4-hydroxytetrahydrofuran-3-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxv) 3-((3S,4S)-4-hydroxytetrahydrofuran-3-yl)-8-(pyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido [ 3,4-d]pyrimidin-4(3H)-one (cxvi)methyl (S)-2-(4-oxo-8-(pyridin-3-yl)-6-(6-(trifluoromethyl)pyridine -3-yl)pyrido[3,4-d]pyrimidin-3(4H)-yl)propanoate (cxvii) 6-(4-chlorophenyl)-3-(4-hydroxy-1-methylpyrrolidin-3-yl) -8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxviii)6-(4-chlorophenyl)-3-((3R,4R)-4-hydroxypyrrolidine -3-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxix)(R)-6-(6-cyclopropylpyridin-3-yl )-8-(1-methyl-1H-pyrazol-4-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)pyrido[3,4-d]pyrimidine-4(3H)- On (cxx)(S)-6-(6-cyclopropylpyridin-3-yl)-8-(1-methyl-1H-pyrazol-4-yl)-3-(3,3,3-trifluoro- 2-hydroxypropyl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxxi) 3-((3S,4R)-4-hydroxytetrahydrofuran-3-yl)-8-(1-methyl- 1H-pyrazol-4-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxxii)3-((3R, 4S)-4-hydroxytetrahydrofuran-3-yl)-8-(1-methyl -1H-pyrazol-4-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxxiii)3-((3S , 4R)-4-hydroxytetrahydrofuran-3-yl)-8-(pyridin-3-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidine- 4(3H)-one (cxxiv) 3-((3R,4S)-4-hydroxytetrahydrofuran-3-yl)-8-(pyridin-3-yl)-6-(5-(trifluoromethyl)pyridine- 2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxxv) (R)-3-(2-hydroxypropyl)-8-(1-methyl-1H-pyrazol-4-yl )-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxxvi)(S)-3-(2-hydroxypropyl)- 8-(1-methyl-1H-pyrazol-4-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxxvii ) (S)-3-(2-hydroxypropyl)-8-(pyridin-3-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidine- 4(3H)-one (cxxviii) (R)-3-(2-hydroxypropyl)-8-(pyridin-3-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido [ 3,4-d]pyrimidin-4(3H)-one (cxxix)3-((3S,4S)-4-hydroxytetrahydrofuran-3-yl)-8-(pyridin-3-yl)-6-(5 -(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxxx)(S)-3-(2-hydroxypropyl)-8-(pyridine-3 -yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxxxi)(S)-8-(1-methyl- 1H-pyrazol-4-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido [3,4-d ] pyrimidin-4(3H)-one (cxxxii)(S)-3-(1-hydroxypropane-2 -yl)-8-(1-methyl-1H-pyrazol-4-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidine-4(3H) -one (cxxxiii) 3-((3S,4S)-4-hydroxytetrahydrofuran-3-yl)-8-(1-methyl-1H-pyrazol-4-yl)-6-(5-(trifluoromethyl) pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxxxiv) 6-(4-chlorophenyl)-3-((3R,4S)-4-hydroxytetrahydrofuran-3-yl )-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxxxv)6-(4-chlorophenyl)-3-((3R,4S)-4-hydroxy Tetrahydrofuran-3-yl)-8-(1-methyl-1H-pyrazol-4-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxxxvi) (R)-8-(pyridine- 3-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidine-4 (3H)-one (cxxxvii)(S)-2-(4-oxo-8-(pyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4 -d]pyrimidin-3(4H)-yl)propanoic acid (cxxxviii) (S)-N-methyl-2-(4-oxo-8-(pyridin-3-yl)-6-(6-(trifluoro methyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-3(4H)-yl)propanamide (cxxxix) (S)-N,N-dimethyl-2-(4-oxo-8-( Pyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-3(4H)-yl)propenamide (cxl) 3-(2- Hydroxy-2-methylpropyl)-8-(1H-pyrazol-4-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidine-4(3H) -one (cxli) 3-(2-hydroxy-2-methylpropyl)-8-(1H-imidazol-1-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido [3, 4-d]pyrimidin-4(3H)-one (cxlii) 3-(2-hydroxy -2-methylpropyl)-8-(1H-imidazol-1-yl)-6-(6-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidine-4(3H)- On (cxliii) (S)-3-(1-hydroxypropan-2-yl)-8-(1H-imidazol-1-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido [3,4-d]pyrimidin-4(3H)-one (cxliv) (S)-3-(1-hydroxypropan-2-yl)-8-(1H-imidazol-1-yl)-6-( 6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxlv)(S)-3-(1-hydroxypropan-2-yl)-8 -(1H-1,2,4-triazol-1-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one ( cxlvi) (S)-3-(1-hydroxypropan-2-yl)-8-(1H-pyrazol-1-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido [3 , 4-d]pyrimidin-4(3H)-one (cxlvii) (S)-3-(1-hydroxypropan-2-yl)-8-(1-methyl-1H-pyrazol-4-yl)-6 -(2-(trifluoromethyl)thiazol-5-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxlviii)(S)-8-(diethylamino)-3-(1-hydroxy Propan-2-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxlix)(S)-3-(1 -hydroxypropan-2-yl)-8-(piperidin-1-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidine-4(3H)- On (cl) (S)-3-(1-hydroxypropan-2-yl)-8-(pyrrolidin-1-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido [3 ,4-d]pyrimidin-4(3H)-one (cli)(S)-6-(4-chlorophenyl)-3-(1-hydroxypropan-2-yl)-8-(piperidin-1-yl) pyrido[3,4-d]pyrimidin-4(3H)-one (clii)(S)-3-(1-hydroxypropan-2-yl)-8- (pyridin-2-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cliiii)(S)-6-cyclohexyl -3-(1-hydroxypropan-2-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cliv)(S)-3-(1 -hydroxypropan-2-yl)-6-(pyridin-2-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (clv) (S) -3-(1-hydroxypropan-2-yl)-6-(2-methylthiazol-4-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidine-4(3H) -one (clvi) (S)-3-(1-hydroxypropan-2-yl)-6-(1-methyl-1H-1,2,3-triazol-5-yl)-8-(pyridin-3 -yl)pyrido[3,4-d]pyrimidin-4(3H)-one (clvii)(R)-6-(4-chlorophenyl)-8-(pyridin-3-yl)-3-(3,3 ,3-trifluoro-2-hydroxypropyl)pyrido[3,4-d]pyrimidin-4(3H)-one;
(clviii) (S)-6-(4-chlorophenyl)-8-(pyridin-3-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)pyrido[3,4-d] pyrimidin-4(3H)-one;
(clix) (S)-3-(1-hydroxypropan-2-yl)-8-(1-methyl-1,2,5,6-tetrahydropyridin-3-yl)-6-(6-(tri fluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one;
(clx) 6-(4-chlorophenyl)-3-((3S,4S)-4-hydroxytetrahydrofuran-3-yl)-8-(1-methyl-1H-pyrazol-4-yl)pyrido[3,4 -d]pyrimidin-4(3H)-one;
(clxi) (S)-3-(1-hydroxypropan-2-yl)-6-(2-methylpyrimidin-5-yl)-8-(pyridin-3-yl)pyrido[3,4-d] pyrimidin-4(3H)-one;
(clxii) 3-(2-hydroxy-2-methylpropyl)-8-(1-(trifluoromethyl)-1H-pyrazol-4-yl)-6-(6-(trifluoromethyl)pyridine-3- yl)pyrido[3,4-d]pyrimidin-4(3H)-one;
(clxiii) (S)-3-(1-hydroxypropan-2-yl)-8-(1-methyl-1H-pyrazol-4-yl)-6-(2-(trifluoromethyl)pyrimidine-5- yl)pyrido[3,4-d]pyrimidin-4(3H)-one;
(clxiv) 3-(2-hydroxy-2-methylpropyl)-8-(pyridin-3-yl)-6-(2-(trifluoromethyl)pyrimidin-5-yl)pyrido[3,4-d] pyrimidin-4(3H)-one;
(clxv) (S)-5-(3-(1-hydroxypropan-2-yl)-4-oxo-8-(pyridin-3-yl)-3,4-dihydropyrido[3,4-d]pyrimidine -6-yl) picolinic acid;
(clxvi) (S)-3-(1-hydroxypropan-2-yl)-6-(6-methylpyridin-3-yl)-8-(pyridin-3-yl)pyrido[3,4-d] pyrimidin-4(3H)-one;
(clxvii) 3-(2-hydroxy-2-methylpropyl)-8-(1-methyl-1H-pyrazol-4-yl)-6-(2-(trifluoromethyl)pyrimidin-5-yl)pyrido [ 3,4-d]pyrimidin-4(3H)-one;
(clxviii) 3,8-di(pyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one;
(clxix) 8-(pyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one;
(clxx) 3-((3R,4R)-4-hydroxytetrahydrofuran-3-yl)-8-(pyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido [ 3,4-d]pyrimidin-4(3H)-one;
(clxxi) 3-((3R,4R)-4-hydroxytetrahydrofuran-3-yl)-8-(1-methyl-1H-pyrazol-4-yl)-6-(6-(trifluoromethyl)pyridine- 3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one;
(clxxii) 6-(4-chlorophenyl)-3-((3R,4R)-4-hydroxytetrahydrofuran-3-yl)-8-(1-methyl-1H-pyrazol-4-yl)pyrido[3,4 -d]pyrimidin-4(3H)-one;
(clxxiii) 3-cyclopentyl-8-(pyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one;
(clxxiv) 3-phenyl-8-(pyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one;
(clxxv) 3-((3R,4R)-4-hydroxytetrahydrofuran-3-yl)-8-(pyridin-3-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido [ 3,4-d]pyrimidin-4(3H)-one;
(clxxvi) 3-((3R,4R)-4-hydroxytetrahydrofuran-3-yl)-8-(1-methyl-1H-pyrazol-4-yl)-6-(5-(trifluoromethyl)pyridine- 2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one;
(clxxvii) (S)-3-(1-hydroxypropan-2-yl)-8-(1-methyl-1H-pyrazol-4-yl)-6-(5-(trifluoromethyl)pyridine-2- yl)pyrido[3,4-d]pyrimidin-4(3H)-one;
(clxxviii) (S)-N-((3R,4S)-4-hydroxytetrahydrofuran-3-yl)-2-(4-oxo-8-(pyridin-3-yl)-6-(6-(tri fluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-3(4H)-yl)propanamide (clxxix) 3-(2-hydroxy-2-methylpropyl)-8-(1H-pyrazole -4-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one;
(clxxx)(S)-6-(4-chlorophenyl)-3-(1-hydroxypropan-2-yl)-8-(1H-pyrazol-1-yl)pyrido[3,4-d]pyrimidine-4 (3H)-on;
(clxxxxi) (S)-3-(1-hydroxypropan-2-yl)-8-(1H-pyrazol-1-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido [ 3,4-d]pyrimidin-4(3H)-one;
(clxxxii) 3-((3S,4R)-4-hydroxytetrahydrofuran-3-yl)-8-(pyridin-3-yl)-6-(2-(trifluoromethyl)thiazol-5-yl)pyrido [ 3,4-d]pyrimidin-4(3H)-one;
(clxxxiii) 3-(2-hydroxy-2-methylpropyl)-8-(1-methyl-1H-pyrazol-4-yl)-6-(2-(trifluoromethyl)thiazol-5-yl)pyrido [ 3,4-d]pyrimidin-4(3H)-one;
(clxxxiv) 3-((3S,4R)-4-hydroxytetrahydrofuran-3-yl)-8-(1-methyl-1H-pyrazol-4-yl)-6-(2-(trifluoromethyl)thiazole- 5-yl)pyrido[3,4-d]pyrimidin-4(3H)-one;
(clxxxv) 3-((3R,4S)-4-hydroxytetrahydrofuran-3-yl)-8-(1-methyl-1H-pyrazol-4-yl)-6-(2-(trifluoromethyl)thiazole- 5-yl)pyrido[3,4-d]pyrimidin-4(3H)-one;
(clxxxvi) 3-((3R,4S)-4-hydroxytetrahydrofuran-3-yl)-8-(pyridin-3-yl)-6-(2-(trifluoromethyl)thiazol-5-yl)pyrido [ 3,4-d]pyrimidin-4(3H)-one;
(clxxxvii) (S)-3-(1-hydroxypropan-2-yl)-8-morpholino-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidine- 4(3H)-on;
(clxxxviii) 3-(2-hydroxy-2-methylpropyl)-8-(piperidin-1-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d] pyrimidin-4(3H)-one;
(clxxxix)(S)-3-(1-hydroxypropan-2-yl)-6-(5-methylpyridin-2-yl)-8-(pyridin-3-yl)pyrido[3,4-d] pyrimidin-4(3H)-one;
(cxc) (S)-3-(1-hydroxypropan-2-yl)-6-(5-methylpyrimidin-2-yl)-8-(pyridin-3-yl)pyrido [3,4-d] pyrimidin-4(3H)-one;
(cxci) (S)-8-(cyclohex-1-en-1-yl)-3-(1-hydroxypropan-2-yl)-6-(5-(trifluoromethyl)pyridin-2-yl) pyrido[3,4-d]pyrimidin-4(3H)-one;
(cxcii) (S)-8-cyclohexyl-3-(1-hydroxypropan-2-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidine- 4(3H)-on;
(cxciii) (S)-3-(1-hydroxypropan-2-yl)-N,N-dimethyl-4-oxo-8-(pyridin-3-yl)-3,4-dihydropyrido[3,4- d] pyrimidine-6-carboxamide;
(cxciv) (S)-3-(1-hydroxypropan-2-yl)-8-(1H-pyrazol-4-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido [ 3,4-d]pyrimidin-4(3H)-one;
(cxcv) (S)-3-(1-hydroxypropan-2-yl)-6-(2-methoxyethyl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidine-4 ( 3H)-one; and (cxcvi)-3-(1-hydroxypropan-2-yl)-8-(2-methoxyethyl)-6-(5-(trifluoromethyl)pyridin-2-yl ) pyrido[3,4-d]pyrimidin-4(3H)-one (cxcvii).

30. A pharmaceutical composition comprising at least one entity selected from the compounds of any one of embodiments 1-29 and pharmaceutically acceptable salts thereof, and at least one pharmaceutically acceptable excipient.

31. A method of treating a disease or condition mediated by AhR signaling in a subject in need thereof comprising administering to the subject a therapeutically effective amount of any of embodiments 1-29 or one compound and pharmaceutically acceptable salts thereof; or at least one pharmaceutical composition of embodiment 30.

32. A method of treating a disease or condition associated with aberrant AhR signaling in a subject in need thereof comprising administering to the subject a therapeutically effective amount of embodiments 1-29 and pharmaceutically acceptable salts thereof, or at least one pharmaceutical composition of embodiment 30.

33. 33. The method of embodiment 31 or 32, wherein the disease is selected from cancer.

34. 33. The method of embodiment 31 or 32, wherein the disease is selected from liquid tumors and solid tumors.

35. Breast cancer, respiratory tract cancer, brain cancer, genital cancer, gastrointestinal cancer, urinary tract cancer, eye cancer, liver cancer, skin cancer, head and neck cancer, thyroid cancer, parathyroid cancer, and any of the above The method of any one of embodiments 31-34, selected from metastasis.

36. 36. The method of any one of embodiments 31-35, wherein the disease is selected from breast cancer, pancreatic cancer, prostate cancer, and colon cancer.

37. The method of any one of embodiments 31-34, wherein the disease is selected from lymphoma, sarcoma, melanoma, glioblastoma, and leukemia.

38. A method of inhibiting cancer cell growth mediated by AhR signaling in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of any of embodiments 1-29 or one compound and pharmaceutically acceptable salts thereof; or at least one pharmaceutical composition of embodiment 30.

39. A method of inhibiting AhR signaling-mediated tumor cell invasion or metastasis in a subject in need thereof, comprising: administering to the subject a therapeutically effective amount of embodiment 1 31. A method comprising administering at least one entity selected from any one of the compounds of -29 and pharmaceutically acceptable salts thereof or at least one pharmaceutical composition of embodiment 30.

40. A method of treating cancer in a subject in need thereof, comprising: administering to said subject a therapeutically effective amount of i) a compound of any one of embodiments 1-29 and a pharmaceutically acceptable salt thereof; 31. A method comprising administering at least one selected entity or at least one pharmaceutical composition of embodiment 30 and ii) a therapeutically effective amount of at least one additional therapy.

41. 41. The method of embodiment 40, wherein the at least one additional therapy comprises at least 2, at least 3, at least 4, or at least 5 additional therapies.

42. Administration of at least one entity selected from compounds of any one of embodiments 1-29 and pharmaceutically acceptable salts thereof or at least one pharmaceutical composition of embodiment 30 is administered with at least one additional 41. The method of embodiment 40, initiated prior to administration of therapy.

43. at least one entity selected from a compound of any one of embodiments 1-29 and pharmaceutically acceptable salts thereof or at least one pharmaceutical composition of embodiment 30 is administered for at least one additional therapy 41. The method of embodiment 40, administered after administration.

44. at least one entity selected from a compound of any one of embodiments 1-29 and pharmaceutically acceptable salts thereof or at least one pharmaceutical composition of embodiment 30 is administered for at least one additional therapy 41. The method of embodiment 40, administered concurrently with administration.

45. 45. The method of any one of embodiments 40-44, wherein the at least one additional therapy is selected from checkpoint inhibitors.

46. 46. The method of embodiment 45, wherein the subject is intolerant, refractory and/or poorly responsive to the at least one additional therapy when the at least one additional therapy is administered alone.

47. Embodiment 46, wherein the at least one additional therapy is selected from checkpoint inhibitors targeting CTLA-4, PD-1, PD-L1, LAG-3, TIM-3, TIGIT, and/or VISTA the method of.

48. 47. The method of embodiment 46, wherein the at least one additional therapy is selected from checkpoint inhibitors targeting CTLA-4, PD-1, and/or PD-L1.

49. 47. The method of embodiment 46, wherein the at least one additional therapy is selected from cytotoxic T lymphocyte-associated antigen 4 pathway inhibitors.

50. The method of embodiment 49, wherein the cytotoxic T lymphocyte-associated antigen 4 pathway inhibitor is selected from anti-CTLA-4 antibodies.

51. 51. The method of embodiment 50, wherein the anti-CTLA-4 antibody is ipilimumab.

52. 47. The method of embodiment 46, wherein the at least one additional therapy is selected from programmed death-1 pathway inhibitors.

53. 53. The method of embodiment 52, wherein the programmed death-1 pathway inhibitor is selected from anti-PD-1 antibodies.

54. 53. The method of embodiment 52, wherein the anti-PD-1 antibody is nivolumab.

55. 53. The method of embodiment 52, wherein the anti-PD-1 antibody is pembrolizumab.

56. 53. The method of embodiment 52, wherein the anti-PD-1 antibody is semiplimab.

57. 53. The method of embodiment 52, wherein the anti-PD-1 antibody is camrelizumab.

58. 53. The method of embodiment 52, wherein the anti-PD-1 antibody is Scintilimab.

59. 53. The method of embodiment 52, wherein the anti-PD-1 antibody is spartalizumab.

60. 53. The method of embodiment 52, wherein the anti-PD-1 antibody is tislelizumab.

61. 53. The method of embodiment 52, wherein the anti-PD-1 antibody is BCD-100.

62. 53. The method of embodiment 52, wherein the anti-PD-1 antibody is JS001.

63. 53. The method of embodiment 52, wherein the programmed death-1 pathway inhibitor is selected from anti-PD-L1 antibodies.

64. 64. The method of embodiment 63, wherein the anti-PD-L1 antibody is atezolizumab.

65. 64. The method of embodiment 63, wherein the anti-PD-L1 antibody is avelumab.

66. 64. The method of embodiment 63, wherein the anti-PD-L1 antibody is durvalumab.

67. 64. The method of embodiment 63, wherein the anti-PD-L1 antibody is KN035.

68. 47. The method of embodiment 46, wherein the at least one additional therapy is selected from lymphocyte activation gene-3 (LAG-3) inhibitors.

69. 69. The method of embodiment 68, wherein the LAG-3 inhibitor is selected from anti-LAG-3 antibodies.

70. 47. The method of embodiment 46, wherein the at least one additional therapy is selected from T cell immunoglobulins and mucin domain containing-3 (TIM-3) inhibitors.

71. 71. The method of embodiment 70, wherein the TIM-3 inhibitor is selected from anti-TIM-3 antibodies.

72. 47. The method of embodiment 46, wherein the at least one additional therapy is selected from T cell immunoglobulins and ITIM domain (TIGIT) inhibitors.

73. 73. The method of embodiment 72, wherein the TIGIT inhibitor is selected from TIGIT antibodies.

74. 47. The method of embodiment 46, wherein the at least one additional therapy is selected from V-domain Ig suppressor of T cell activation (VISTA) inhibitors.

75. 75. The method of embodiment 74, wherein the VISTA inhibitor is selected from anti-VISTA antibodies.

76. Head and neck squamous cell carcinoma; renal cell carcinoma; gastric adenocarcinoma; nasopharyngeal neoplasm; urothelial carcinoma; colorectal cancer; Breast cancer (TNBC); esophageal neoplasms; multiple myeloma; gastric and esophagogastric junction cancer; melanoma; Epithelial lung cancer; mesothelioma; gastric cancer; esophagogastric junction cancer; metastatic melanoma; metastatic noncutaneous melanoma; transitional cell carcinoma; prostate neoplasm; recurrent or metastatic PD-L1 positive or negative squamous cell carcinoma of the head and neck (SCCHN); recurrent squamous cell lung cancer SCCHN; hypopharyngeal squamous cell carcinoma; laryngeal squamous cell carcinoma; unresectable or metastatic melanoma; biliary tract neoplasm; 76. The method of any one of embodiments 40-75, selected from cancer, solid organ cancer; gastric cancer; colon cancer; and liver cancer.

The following non-limiting examples and data illustrate various aspects and features associated with the compounds and/or methods of this disclosure, including the preparation of various compounds available by the synthetic methods described herein. do. Compared to the prior art, in some embodiments, the compounds and/or methods provide surprising, unexpected, and contrasting results and data. Although the utility of this disclosure is illustrated by the use of several compounds and moieties/groups that can be used with it, equivalent results may be obtained from various other compounds, moieties, and/or moieties commensurate in scope with this disclosure. It will be understood by those skilled in the art that it is obtained from the group

Example 1. Synthesis of Pyridopyrimidinone Compounds Compounds encompassed within this disclosure can be prepared by the procedures outlined in Scheme I and described in the Examples below.

ｔｅｒｔ－ブチルＮ－［（１Ｓ）－２－ヒドロキシ－１－メチル－エチル］カルバメート（８、１０ｇ、５７ｍｍｏｌ、１当量）のＴＨＦ（３００ｍＬ）溶液に、ＮａＨ（２．５１ｇ、６２．７８ｍｍｏｌ、純度６０％、１．１当量）を０℃で加え、混合物を０℃で３０分間撹拌した。ＢｎＢｒ（１１．７１ｇ、６８．４８ｍｍｏｌ、８．１３ｍＬ、１．２当量）及びテトラブチルアンモニウムヨージド（２１０．８０ｍｇ、５７０．６９ｕｍｏｌ、０．０１当量）を０℃の混合物に加え、次いで、混合物を２５℃で３時間撹拌した。反応混合物を０℃のＭｅＯＨ（５０ｍＬ）の添加によりクエンチし、次いで濾過し、濾液を減圧下で濃縮すると、残渣を与えた。残渣をカラムクロマトグラフィー（ＳｉＯ２、石油エーテル／酢酸エチル＝１／０～０／１）により精製すると、標記化合物を得た（１２ｇ、４５．２２ｍｍｏｌ、収率７９％）。１Ｈ ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３），δ ｐｐｍ １．２０（ｄ，Ｊ＝６．８Ｈｚ，３Ｈ），１．４５（ｓ，９Ｈ），３．３５－３．４８（ｍ，２Ｈ），３．８０－３．９４（ｍ，１Ｈ）， ４．４８（ｑ，Ｊ＝１２．０，１７．６Ｈｚ，２Ｈ），４．６７－４．８０（ｍ，１Ｈ），７．２７－７．３８（ｍ，５Ｈ）． Preparation of tert-butyl N-[(1S)-2-benzyloxy-1-methyl-ethyl]carbamate:

To a solution of tert-butyl N-[(1S)-2-hydroxy-1-methyl-ethyl]carbamate (8, 10 g, 57 mmol, 1 eq) in THF (300 mL) was added NaH (2.51 g, 62.78 mmol, pure 60%, 1.1 eq) was added at 0°C and the mixture was stirred at 0°C for 30 minutes. BnBr (11.71 g, 68.48 mmol, 8.13 mL, 1.2 eq) and tetrabutylammonium iodide (210.80 mg, 570.69 umol, 0.01 eq) were added to the mixture at 0° C. and then the mixture was stirred at 25° C. for 3 hours. The reaction mixture was quenched by the addition of MeOH (50 mL) at 0° C., then filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether/ethyl acetate=1/0 to 0/1) to give the title compound (12 g, 45.22 mmol, 79% yield). 1H NMR (400 MHz, CDCl3), δ ppm 1.20 (d, J = 6.8 Hz, 3H), 1.45 (s, 9H), 3.35-3.48 (m, 2H), 3.80 -3.94 (m, 1H), 4.48 (q, J = 12.0, 17.6Hz, 2H), 4.67-4.80 (m, 1H), 7.27-7.38 ( m, 5H).

ｔｅｒｔ－ブチルＮ－［（１Ｓ）－２－ベンジルオキシ－１－メチル－エチル］カルバメート（９、１２ｇ、４５．２２ｍｍｏｌ、１当量）のＤＣＭ（１００ｍＬ）溶液に、ＴＦＡ（３０．８０ｇ、２７０．１２ｍｍｏｌ、２０ｍＬ、５．９７当量）を滴加した。混合物を２５℃で３時間撹拌した。反応混合物を減圧下で濃縮すると、標記化合物を得て（１０、１０ｇ、３５．８１ｍｍｏｌ、収率７９．１８％、ＴＦＡ）、それを直接使用した。 Preparation of (2S)-1-benzyloxypropan-2-aminetrifluoroacetic acid:

To a solution of tert-butyl N-[(1S)-2-benzyloxy-1-methyl-ethyl]carbamate (9, 12 g, 45.22 mmol, 1 eq) in DCM (100 mL) was added TFA (30.80 g, 270. 12mmol, 20mL, 5.97eq) was added dropwise. The mixture was stirred at 25° C. for 3 hours. The reaction mixture was concentrated under reduced pressure to give the title compound (10, 10 g, 35.81 mmol, 79.18% yield, TFA), which was used directly.

３－アミノ－２，６－ジクロロイソニコチン酸（２．０ｇ、９．６６ｍｍｏｌ）及び（Ｓ）－２－アミノプロパン－１－オール（反応物１、０．８０ｇ、１０．６３ｍｍｏｌ）の混合物をＤＭＦ（３２．２ｍＬ）に溶解させ、反応混合物を０℃に冷却した。ジイソプロピルエチルアミン（３．３７ｍＬ、１９．３ｍｍｏｌ）及びＨＡＴＵ （４．４１ｇ、１１．５９ｍｍｏｌ）を加え、反応物を０℃で１時間撹拌した。反応物を水でクエンチし、酢酸エチルと水との間で分配した。有機相を分離し、飽和塩化アンモニウム水溶液で、次いで飽和炭酸水素ナトリウム水溶液で洗浄し、無水硫酸マグネシウムで乾燥させ、濾過し、蒸発させた。残渣を、酢酸エチル／ヘキサンを使用するシリカゲルクロマトグラフィーにより精製すると、標記化合物を与えた（１．８２ｇ、６．８９ｍｍｏｌ、収率７１％）。^１Ｈ ＮＭＲ（ＣＨ_３ＯＨ－ｄ４，４００ＭＨｚ）δ １．２１（３Ｈ，ｄ，Ｊ＝６．８Ｈｚ），３．５８－３．５６（２Ｈ，ｍ），４．１７－４．１２（１Ｈ，ｍ），７．４９（１Ｈ，ｓ）；ＭＳ（ｍ／ｚ）：２６５．１ ［Ｍ＋Ｈ］^＋． (S)-8-(5-fluoropyridin-3-yl)-3-(1-hydroxypropan-2-yl)-6-(4-(trifluoromethoxy)phenyl)pyrido[3,4-d] Steps for the preparation of pyrimidin-4(3H)-one (1) 1. Preparation of (S)-3-amino-2,6-dichloro-N-(1-hydroxypropan-2-yl)isonicotinamide (Intermediate A1):

A mixture of 3-amino-2,6-dichloroisonicotinic acid (2.0 g, 9.66 mmol) and (S)-2-aminopropan-1-ol (Reactant 1, 0.80 g, 10.63 mmol) was Dissolve in DMF (32.2 mL) and cool the reaction mixture to 0°C. Diisopropylethylamine (3.37 mL, 19.3 mmol) and HATU (4.41 g, 11.59 mmol) were added and the reaction was stirred at 0° C. for 1 hour. The reaction was quenched with water and partitioned between ethyl acetate and water. The organic phase was separated, washed with saturated aqueous ammonium chloride solution and then with saturated aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium sulphate, filtered and evaporated. The residue was purified by silica gel chromatography using ethyl acetate/hexanes to give the title compound (1.82 g, 6.89 mmol, 71% yield). ¹ H NMR (CH OH _- d4, 400 MHz) δ 1.21 (3H, d, J = 6.8 Hz), 3.58-3.56 (2H, m), 4.17-4.12 (1H , m), 7.49 (1 H, s); MS (m/z): 265.1 [M+H] ⁺ .

Table 2 lists intermediates prepared by procedures similar to those described in Step 1 above.

プロピルホスホン酸無水物（Ｔ３Ｐ、６４．６ｇ、１０１ｍｍｏｌ、６０．３ｍＬ、純度５０％、１．０５当量）を、３－アミノ－２，６－ジクロロイソニコチン酸（試薬１、２０ｇ、９６．６ｍｍｏｌ、１当量）、（３Ｓ，４Ｒ）－４－アミノテトラヒドロフラン－３－オール（１０．５ｇ、１０１ｍｍｏｌ、１．０５当量）、及びトリエチルアミン（２９．３ｇ、２９０ｍｍｏｌ、４０．３ｍＬ、３当量）のＥｔＯＡｃ（１５０ｍＬ）溶液に一度に加えた。生じた溶液を２５℃で１時間攪拌した。反応物を水（１００ｍＬ）に注いだ。有機相を回収し、水相をＥｔＯＡｃ（３０ｍＬ×２）により抽出した。合わせた有機相をブライン（１００ｍＬ）で洗浄し、真空下で濃縮すると、標記化合物３－アミノ－２，６－ジクロロ－Ｎ－（（３Ｒ，４Ｓ）－４－ヒドロキシテトラヒドロフラン－３－イル）イソニコチンアミド（Ａ１６、２５ｇ、８５．６ｍｍｏｌ、収率８８．６％）を灰白色の固体として与えた。粗生成物を精製せずに次の工程に使用した。^１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤ_３ＯＤ）：δ_Ｈ ｐｐｍ ７．４９（ｓ，１Ｈ），４．２８－４．３４（ｍ，２Ｈ），４．１０－４．１７（ｍ，１Ｈ），４．０２（ｄｄ，Ｊ＝１０．０Ｈｚ，Ｊ＝４．４Ｈｚ，１Ｈ），３．７３－３．７８（ｍ，１Ｈ），３．６５－３．７０（ｍ，１Ｈ）；ＭＳ（ｍ／ｚ）：２９０．０ ［Ｍ＋Ｈ］^＋． Preparation of 3-amino-2,6-dichloro-N-((3R,4S)-4-hydroxytetrahydrofuran-3-yl)isonicotinamide (A16)

Propylphosphonic anhydride (T3P, 64.6 g, 101 mmol, 60.3 mL, 50% purity, 1.05 eq) was added to 3-amino-2,6-dichloroisonicotinic acid (Reagent 1, 20 g, 96.6 mmol). , 1 eq), (3S,4R)-4-aminotetrahydrofuran-3-ol (10.5 g, 101 mmol, 1.05 eq), and triethylamine (29.3 g, 290 mmol, 40.3 mL, 3 eq) in EtOAc (150 mL) was added to the solution in one portion. The resulting solution was stirred at 25° C. for 1 hour. The reaction was poured into water (100 mL). The organic phase was collected and the aqueous phase was extracted with EtOAc (30 mL x 2). The combined organic phases are washed with brine (100 mL) and concentrated in vacuo to give the title compound 3-amino-2,6-dichloro-N-((3R,4S)-4-hydroxytetrahydrofuran-3-yl)iso Nicotinamide (A16, 25 g, 85.6 mmol, 88.6% yield) was provided as an off-white solid. The crude product was used for next step without purification. ¹ H-NMR (400 MHz, CD ₃ OD): δ _H ppm 7.49 (s, 1H), 4.28-4.34 (m, 2H), 4.10-4.17 (m, 1H), 4.02 (dd, J = 10.0 Hz, J = 4.4 Hz, 1H), 3.73-3.78 (m, 1H), 3.65-3.70 (m, 1H); /z): 290.0 [M+H] ⁺ .

フラスコ内の（Ｓ）－３－アミノ－２，６－ジクロロ－Ｎ－（１－ヒドロキシプロパン－２－イル）イソニコチンアミド（Ａ１、２．５４ｇ、９．６６ｍｍｏｌ）に、オルトギ酸トリエチル（２０ｍＬ）を加えた。濃塩化水素酸（０．８ｍＬ、９．７ｍｍｏｌ）をゆっくりと室温で滴加し、生じた混合物を２時間撹拌した。混合物を濃縮し、固体を真空濾過により回収し、水で洗浄し、高真空下で乾燥させると、標記化合物を与えた（Ｂ１、１．８２ｇ、６．６４ｍｍｏｌ、収率６９％）。１Ｈ ＮＭＲ（ＣＨ３ＯＨ－ｄ４，４００ＭＨｚ）δ １．５１（３Ｈ，ｄ，Ｊ＝７．１Ｈｚ），３．８０（１Ｈ，ｄｄ，Ｊ＝１１．９，４．２Ｈｚ），３．９２（１Ｈ，ｄｄ，Ｊ＝１１．９，６．９Ｈｚ），４．９３－４．８８（１Ｈ，ｍ），８．０５（１Ｈ，ｓ），８．４５（１Ｈ，ｓ）；ＭＳ（ｍ／ｚ）：２７４．０［Ｍ＋Ｈ］＋． Step 2. Preparation of (S)-6,8-dichloro-3-(1-hydroxypropan-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (Intermediate B1):

To (S)-3-amino-2,6-dichloro-N-(1-hydroxypropan-2-yl)isonicotinamide (A1, 2.54 g, 9.66 mmol) in a flask was added triethyl orthoformate (20 mL). ) was added. Concentrated hydrochloric acid (0.8 mL, 9.7 mmol) was slowly added dropwise at room temperature and the resulting mixture was stirred for 2 hours. The mixture was concentrated and the solid was collected by vacuum filtration, washed with water and dried under high vacuum to give the title compound (B1, 1.82 g, 6.64 mmol, 69% yield). 1H NMR (CHOH-d4, 400MHz) δ 1.51 (3H, d, J = 7.1Hz), 3.80 (1H, dd, J = 11.9, 4.2Hz), 3.92 (1H, dd, J=11.9, 6.9 Hz), 4.93-4.88 (1 H, m), 8.05 (1 H, s), 8.45 (1 H, s); MS (m/z) : 274.0 [M+H]+.

ギ酸（１８．９４ｇ、４１１．４１ｍｍｏｌ、１５．５２ｍＬ、１．５当量）を、０℃の酢酸アセチル（２８ｇ、２７４．２７ｍｍｏｌ、２５．６９ｍＬ、１当量）に滴加し、６０℃で２時間、Ｎ_２雰囲気下で撹拌した。無色の液体として溶液が得られ（４１ｍＬ、６．６５Ｍ）、さらに精製せずに次の工程に使用した。３－アミノ－Ｎ－［（１Ｓ）－２－ベンジルオキシ－１－メチル－エチル］－２，６－ジクロロ－ピリジン－４－カルボキサミド（Ａ１１、４．５ｇ、１２．７０ｍｍｏｌ、１当量）のＴＨＦ（５０ｍＬ）溶液に、酢酸ホルミル溶液（６．６５Ｍ、４１ｍＬ、２１．４７当量）を２５℃で加え、６０℃で３０分間撹拌した。次いで、混合物を１００℃で９．５時間撹拌した。ＬＣＭＳは、所望の化合物が検出されたことを示した。反応混合物を減圧下で濃縮すると、残渣を与えた。残渣をＥｔＯＡｃ（５０ｍＬ）で希釈し、飽和ＮａＨＣＯ_３（２００ｍＬ）、水（５０ｍＬ）、及びブライン（５０ｍＬ）により連続的に洗浄し、Ｎａ_２ＳＯ_４で乾燥させ、濾過し、濾液を減圧下で濃縮すると残渣を与えた。残渣をカラムクロマトグラフィー（ＳｉＯ２、石油エーテル／酢酸エチル＝１／０～１／１）により精製すると、標記化合物を得た（Ｂ１１、２．４ｇ、６．５９ｍｍｏｌ、収率５１．８８％）。^１Ｈ ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ ｐｐｍ １．５６（ｄ，Ｊ＝７．２Ｈｚ，３Ｈ），３．６５－３．７９（ｍ，２Ｈ），４．５０（ｑ，Ｊ＝１２．４，１８．８Ｈｚ，２Ｈ），５．０８－５．２０（ｍ，１Ｈ），７．２０－７．３１（ｍ，５Ｈ），８．０２（ｓ，１Ｈ），８．４１（ｓ，１Ｈ）；ＭＳ：Ｍ＋Ｈ^＋，３６４．０． Preparation of 3-[(1S)-2-benzyloxy-1-methyl-ethyl]-6,8-dichloro-pyrido[3,4-d]pyrimidin-4-one (Intermediate B11)

Formic acid (18.94 g, 411.41 mmol, 15.52 mL, 1.5 eq) was added dropwise to acetyl acetate (28 g, 274.27 mmol, 25.69 mL, 1 eq) at 0°C and stirred at 60°C for 2 hours. , and stirred under _N2 atmosphere. A solution was obtained (41 mL, 6.65 M) as a colorless liquid and used in the next step without further purification. 3-Amino-N-[(1S)-2-benzyloxy-1-methyl-ethyl]-2,6-dichloro-pyridine-4-carboxamide (A11, 4.5 g, 12.70 mmol, 1 eq) in THF To the (50 mL) solution was added formyl acetate solution (6.65 M, 41 mL, 21.47 eq) at 25° C. and stirred at 60° C. for 30 minutes. The mixture was then stirred at 100° C. for 9.5 hours. LCMS indicated the desired compound was detected. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was diluted with EtOAc (50 mL), washed successively with saturated NaHCO ₃ (200 mL), water (50 mL), and brine (50 mL), dried over Na ₂ SO ₄ , filtered, and the filtrate was evaporated under reduced pressure. Concentration gave a residue. The residue was purified by column chromatography (SiO2, petroleum ether/ethyl acetate=1/0 to 1/1) to give the title compound (B11, 2.4 g, 6.59 mmol, 51.88% yield). ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 1.56 (d, J = 7.2 Hz, 3H), 3.65-3.79 (m, 2H), 4.50 (q, J = 12.4 , 18.8 Hz, 2H), 5.08-5.20 (m, 1H), 7.20-7.31 (m, 5H), 8.02 (s, 1H), 8.41 (s, 1H) ); MS: M+H ⁺ , 364.0.

Table 3 lists intermediates prepared by procedures analogous to those described for the synthesis of Intermediate B1 above.

４－メチルベンゼンスルホン酸（１４１．４６ｍｇ、８２１．４６ｍｍｏｌ）を、オルトギ酸トリメチル（１０ｍＬ）中の（Ｓ）－３－アミノ－２，６－ジクロロ－Ｎ－（１－ヒドロキシ－３－メチルブタン－２－イル）イソニコチンアミド（１．２ｇ、４．１１ｍｍｏｌ）の混合物に加え、３回脱気及び窒素置換した。混合物を、１２０℃で８時間、窒素雰囲気下で撹拌した。ＴＬＣは、出発反応物が残っており、２つの新たなスポットが形成されたことを示した。溶媒を蒸発させ、残渣を酢酸エチル（２０ｍＬ）に吸収させ、ブライン（１０ｍＬ）により３回洗浄し、無水硫酸ナトリウムで乾燥させ、濾過し、蒸発させる。残渣を分取ＨＰＬＣにより精製すると、標記化合物（Ｓ）－６，８－ジクロロ－３－（１－ヒドロキシ－３－メチルブタン－２－イル）ピリド［３，４－ｄ］ピリミジン－４（３Ｈ）－オンを与えた（６００ｍｇ、１．９９ｍｍｏｌ、収率４８％）。^１Ｈ－ＮＭＲ（４００ＭＨｚ，ＤＭＳＯ－ｄ_６）：δ_Ｈ ｐｐｍ ８．６０（ｓ，１Ｈ），８．０５（ｓ，１Ｈ），５．０２（ｄ，Ｊ＝３．２Ｈｚ，１Ｈ），４．１９－４．５６（ｍ，１Ｈ），３．８５－３．９７（ｍ，１Ｈ），３．７４（ｑ，Ｊ＝１１．８Ｈｚ，Ｊ＝３．４Ｈｚ，１Ｈ），２．２３－２．３８（ｍ，１Ｈ），１．０４（ｄ，Ｊ＝６．６Ｈｚ，３Ｈ），０．７５（ｄ，Ｊ＝６．６Ｈｚ，３Ｈ）；ＭＳ（ｍ／ｚ）：３０２．０ ［Ｍ＋Ｈ］^＋；９０％純度． Preparation of (S)-6,8-dichloro-3-(1-hydroxy-3-methylbutan-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (B10)

4-Methylbenzenesulfonic acid (141.46 mg, 821.46 mmol) was treated with (S)-3-amino-2,6-dichloro-N-(1-hydroxy-3-methylbutane- in trimethyl orthoformate (10 mL). Added to a mixture of 2-yl)isonicotinamide (1.2 g, 4.11 mmol) and degassed and purged with nitrogen three times. The mixture was stirred at 120° C. for 8 hours under a nitrogen atmosphere. TLC indicated starting reaction remained and two new spots formed. The solvent is evaporated and the residue is taken up in ethyl acetate (20 mL), washed three times with brine (10 mL), dried over anhydrous sodium sulphate, filtered and evaporated. Purification of the residue by preparative HPLC gives the title compound (S)-6,8-dichloro-3-(1-hydroxy-3-methylbutan-2-yl)pyrido[3,4-d]pyrimidine-4(3H) -one (600 mg, 1.99 mmol, 48% yield). ¹ H-NMR (400 MHz, DMSO-d ₆ ): δ _H ppm 8.60 (s, 1H), 8.05 (s, 1H), 5.02 (d, J = 3.2Hz, 1H), 4 .19-4.56 (m, 1H), 3.85-3.97 (m, 1H), 3.74 (q, J = 11.8Hz, J = 3.4Hz, 1H), 2.23- 2.38 (m, 1H), 1.04 (d, J = 6.6Hz, 3H), 0.75 (d, J = 6.6Hz, 3H); MS (m/z): 302.0 [ M+H] ⁺ ; 90% purity.

密封したチューブ内の（Ｓ）－６，８－ジクロロ－３－（１－ヒドロキシプロパン－２－イル）ピリド［３，４－ｄ］ピリミジン－４（３Ｈ）－オン（Ｂ１、０．１０ｇ、０．３７ｍｍｏｌ）、（５－フルオロピリジン－３－イル）ボロン酸（反応物２、０．０５７ｇ、０．４０１ｍｍｏｌ）、炭酸ナトリウム（０．１６ｇ、１．４６ｍｍｏｌ）、及びテトラキス（トリフェニルホスフィン）パラジウム（０．０４２ｇ、０．０３６ｍｍｏｌ）の混合物をアルゴンで置換した。トルエン（３．０ｍＬ）及びエタノール（１．５ｍＬ）を加え、生じた混合物を７５℃で１５時間撹拌した。混合物を室温に冷却し、Ｃｅｌｉｔｅに通して濾過し、Ｃｅｌｉｔｅパッドを酢酸エチルにより洗浄し、濾液を濃縮乾固した。メタノール／ジクロロメタンを使用するシリカゲルクロマトグラフィーによる残渣の精製は標記化合物を与えた（Ｃ１、０．０７８ｇ、０．１９ｍｍｏｌ、収率５３％）。１Ｈ ＮＭＲ（ＤＭＳＯ－ｄ６，３００ＭＨｚ）：δ １．４１（３Ｈ，ｄ，Ｊ＝７．０Ｈｚ），３．６９－３．６２（１Ｈ，ｍ），３．８２－３．７４（１Ｈ，ｍ），４．８９－４．８３（１Ｈ，ｍ），５．０６（１Ｈ，ｔ，Ｊ＝５．６Ｈｚ），８．１２（１Ｈ，ｓ），８．３８（１Ｈ，ｄｄｄ，Ｊ＝１０．２，２．８，１．７Ｈｚ），８．６０（１Ｈ，ｓ），８．７３（１Ｈ，ｄ，Ｊ＝２．８Ｈｚ），９．１４（１Ｈ，ｓ）．；ＭＳ（ｍ／ｚ）：３３５．１［Ｍ＋Ｈ］＋． Step 3. (S)-6-chloro-8-(5-fluoropyridin-3-yl)-3-(1--2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (intermediate Preparation of C1):

(S)-6,8-dichloro-3-(1-hydroxypropan-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (B1, 0.10 g, in a sealed tube, 0.37 mmol), (5-fluoropyridin-3-yl)boronic acid (reactant 2, 0.057 g, 0.401 mmol), sodium carbonate (0.16 g, 1.46 mmol), and tetrakis(triphenylphosphine) A mixture of palladium (0.042 g, 0.036 mmol) was purged with argon. Toluene (3.0 mL) and ethanol (1.5 mL) were added and the resulting mixture was stirred at 75° C. for 15 hours. The mixture was cooled to room temperature, filtered through Celite, the Celite pad was washed with ethyl acetate and the filtrate was concentrated to dryness. Purification of the residue by silica gel chromatography using methanol/dichloromethane gave the title compound (C1, 0.078 g, 0.19 mmol, 53% yield). 1H NMR (DMSO-d6, 300 MHz): δ 1.41 (3H, d, J = 7.0 Hz), 3.69-3.62 (1H, m), 3.82-3.74 (1H, m ), 4.89-4.83 (1H, m), 5.06 (1H, t, J = 5.6 Hz), 8.12 (1H, s), 8.38 (1H, ddd, J = 10 .2, 2.8, 1.7 Hz), 8.60 (1 H, s), 8.73 (1 H, d, J=2.8 Hz), 9.14 (1 H, s). MS (m/z): 335.1 [M+H]+.

Table 4 lists intermediates prepared by procedures similar to those described in Step 3 above.

密封したチューブ内の（Ｓ）－６－クロロ－８－（５－フルオロピリジン－３－イル）－３－（１－ヒドロキシプロパン－２－イル）ピリド［３，４－ｄ］ピリミジン－４（３Ｈ）－オン（Ｃ１、０．０２３ｇ、０．０６９ｍｍｏｌ）、（４－（トリフルオロメトキシ）フェニル）ボロン酸（反応物３、０．０１６ｇ、０．０７６ｍｍｏｌ）、炭酸ナトリウム（０．０２９ｇ、０．２７５ｍｍｏｌ）、及びテトラキス（トリフェニルホスフィン）パラジウム（０．００８ｇ、０．００７ｍｍｏｌ）の混合物をアルゴンで置換した。トルエン（１．０ｍＬ）及びエタノール（０．５ｍＬ）を加え、生じた混合物を７５℃で１５時間撹拌した。混合物を室温に冷却し、Ｃｅｌｉｔｅに通して濾過し、Ｃｅｌｉｔｅパッドを酢酸エチルにより洗浄し、濾液を蒸発させた。メタノール／ジクロロメタンを使用するシリカゲルクロマトグラフィーによる残渣の精製は標記化合物を与えた（０．０２２ｇ、０．０４７ｍｍｏｌ、収率６８％）。^１Ｈ ＮＭＲ（ＤＭＳＯ－ｄ_６，４００ＭＨｚ）：δ １．４４（３Ｈ，ｄ，Ｊ＝７．０Ｈｚ），３．７２－３．６６（１Ｈ，ｍ），３．８４－３．７８（１Ｈ，ｍ），４．９１（１Ｈ，ｓ），５．０８（１Ｈ，ｔ，Ｊ＝５．６Ｈｚ），７．５３（２Ｈ，ｄ，Ｊ＝８．４Ｈｚ），８．４３（２Ｈ，ｄ，Ｊ＝８．６Ｈｚ），８．５３（１Ｈ，ｄｄｄ，Ｊ＝１０．３，２．９，１．７Ｈｚ），８．６０（２Ｈ，ｄ，Ｊ＝３．７Ｈｚ），８．７３（１Ｈ，ｄ，Ｊ＝２．８Ｈｚ），９．２９（１Ｈ，ｓ）；ＭＳ（ｍ／ｚ）：４６１．１ ［Ｍ＋Ｈ］＋；＞９９％純度． Step 4. (S)-8-(5-fluoropyridin-3-yl)-3-(1-hydroxypropan-2-yl)-6-(4-(trifluoromethoxy)phenyl)pyrido[3,4-d] Preparation of pyrimidin-4(3H)-one (1):

(S)-6-Chloro-8-(5-fluoropyridin-3-yl)-3-(1-hydroxypropan-2-yl)pyrido[3,4-d]pyrimidine-4 ( 3H)-one (C1, 0.023 g, 0.069 mmol), (4-(trifluoromethoxy)phenyl)boronic acid (Reactant 3, 0.016 g, 0.076 mmol), sodium carbonate (0.029 g, 0 .275 mmol) and tetrakis(triphenylphosphine)palladium (0.008 g, 0.007 mmol) was purged with argon. Toluene (1.0 mL) and ethanol (0.5 mL) were added and the resulting mixture was stirred at 75° C. for 15 hours. The mixture was cooled to room temperature, filtered through Celite, the Celite pad washed with ethyl acetate and the filtrate evaporated. Purification of the residue by silica gel chromatography using methanol/dichloromethane gave the title compound (0.022 g, 0.047 mmol, 68% yield). ¹ H NMR (DMSO _- d , 400 MHz): δ 1.44 (3H, d, J = 7.0 Hz), 3.72-3.66 (1H, m), 3.84-3.78 (1H , m), 4.91 (1H, s), 5.08 (1H, t, J = 5.6 Hz), 7.53 (2H, d, J = 8.4 Hz), 8.43 (2H, d , J = 8.6 Hz), 8.53 (1H, ddd, J = 10.3, 2.9, 1.7 Hz), 8.60 (2H, d, J = 3.7 Hz), 8.73 ( 1H, d, J=2.8 Hz), 9.29 (1H, s); MS (m/z): 461.1 [M+H]+; >99% purity.

Table 5 lists compounds prepared by procedures analogous to those described for 1, substituting reactants 1, 2, and 3 for the groups indicated.

Ｎ_２下の（Ｓ）－３－（１－ヒドロキシプロパン－２－イル）－８－（１－メチル－１，２，５，６－テトラヒドロピリジン－３－イル）－６－（６－（トリフルオロメチル）ピリジン－３－イル）ピリド［３，４－ｄ］ピリミジン－４（３Ｈ）－オン（６０ｍｇ、０．１３５ｍｍｏｌ）のＥｔＯＨ（１ｍＬ）溶液に、ＰｔＯ_２（１５ｍｇ、０．０８８ｍｍｏｌ）を加えた。フラスコを脱気して、バルーン内のＨ_２ガスに付した。一晩後、反応混合物をＣｅｌｉｔｅ（登録商標）に通して濾過し、メタノールにより充分に洗浄し、濃縮し、Ｈ_２Ｏ中０．１％ギ酸及びアセトニトリルにより溶出する逆相クロマトグラフィーにより精製すると、所望の生成物をジアステレオマー混合物として与えた（４ｍｇ、７％）。^１Ｈ ＮＭＲ（ＣＨ_３ＯＨ－ｄ_４，４００ＭＨｚ）：δ_Ｈ １．２９（１Ｈ，ｓ），１．５４（４Ｈ，ｄ，Ｊ＝７．１Ｈｚ），１．９４（２Ｈ，ｓ），２．１３（１Ｈ，ｓ），２．５０（３Ｈ，ｓ），３．１３（２Ｈ，ｓ），３．８５（１Ｈ，ｓ），３．９５（２Ｈ，ｓ），４．２８（１Ｈ，ｓ），４．６２（２Ｈ，ｓ），４．９９（２Ｈ，ｍ），７．９６（１Ｈ，ｄ，Ｊ＝８．２Ｈｚ），８．４７（１Ｈ，ｓ），８．６０（１Ｈ，ｓ），８．８０（１Ｈ，ｄ，Ｊ＝８．２Ｈｚ），９．５１（１Ｈ，ｓ）．ＭＳ（ｍ／ｚ）：４４８．２ ［Ｍ＋Ｈ］^＋；＞９０％純度． 3-((S)-1-hydroxypropan-2-yl)-8-(1-methylpiperidin-3-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido [3, Preparation of 4-d]pyrimidin-4(3H)-ones

(S)-3-(1-Hydroxypropan- ₂ -yl)-8-(1-methyl-1,2,5,6-tetrahydropyridin-3-yl)-6-(6-(6-( To a solution of trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (60 mg, 0.135 mmol) in EtOH (1 mL) was added PtO ₂ (15 mg, 0.088 mmol). was added. _The flask was evacuated and subjected to H2 gas in a balloon. After overnight, the reaction mixture was filtered through Celite®, washed well with methanol, concentrated, and purified by reverse-phase chromatography, eluting with 0.1% formic acid in H ₂ O and acetonitrile, The desired product was given as a mixture of diastereomers (4mg, 7%). ¹ H NMR (CH ₃ OH-d ₄ , 400 MHz): δ _H 1.29 (1 H, s), 1.54 (4 H, d, J=7.1 Hz), 1.94 (2 H, s), 2 .13 (1H, s), 2.50 (3H, s), 3.13 (2H, s), 3.85 (1H, s), 3.95 (2H, s), 4.28 (1H, s), 4.62 (2H, s), 4.99 (2H, m), 7.96 (1H, d, J = 8.2 Hz), 8.47 (1H, s), 8.60 (1H , s), 8.80 (1 H, d, J=8.2 Hz), 9.51 (1 H, s). MS (m/z): 448.2 [M+H] ⁺ ; >90% purity.

密封したチューブ内の（Ｓ）－６－クロロ－３－（１－ヒドロキシプロパン－２－イル）－８－（ピリジン－３－イル）ピリド［３，４－ｄ］ピリミジン－４（３Ｈ）－オン（１１、０．０６０ｇ、０．１９ｍｍｏｌ）、炭酸カリウム（０．０１１ｇ、０．７６ｍｍｏｌ）に、ジメチルホルムアミド（２．０ｍｌ）を加え、それに続いてモルホリン（０．０３８ｇ、０．３８ｍｍｏｌ）を加えた。生じた混合物を１２０℃で撹拌した。２４時間後、さらなるモルホリン（３８．１ｍｇ、０．３８ｍｍｏｌ）を加え、撹拌を、さらに２４時間１２０℃で続けた。反応混合物を室温に放冷し、次いで水と酢酸エチルとの間で分配した。有機層を分離し、硫酸ナトリウムで乾燥させ、濃縮した。メタノール／ジクロロメタンを使用するシリカゲルクロマトグラフィーによる残渣の精製は標記化合物を与えた（０．０２６ｇ、０．０７１ｍｍｏｌ、収率３７％）。^１Ｈ ＮＭＲ（ＤＭＳＯ－ｄ_６，４００ＭＨｚ）：δ １．３８（３Ｈ，ｄ，Ｊ＝７．０４Ｈｚ），３．５８－３．６５（５Ｈ，ｍ），３．７６（５Ｈ，ｔ，Ｊ＝４．８０Ｈｚ），４．８２－４．８７（１Ｈ，ｍ），７．３０（１Ｈ，ｓ）；５．０３（１Ｈ，ｓ），７．５２（１Ｈ，ｄｄ，Ｊ＝７．９６；４．８１Ｈｚ），８．２３（１Ｈ，ｓ），８．４６（１Ｈ，ｄｔ，Ｊ＝７．９７；１．９７Ｈｚ），８．６３（１Ｈ，ｄｄ，Ｊ＝４．７９；１．７５Ｈｚ），９．２６（１Ｈ，ｄ，Ｊ＝２．１１Ｈｚ）；ＭＳ（ｍ／ｚ）：３６８．２ ［Ｍ＋Ｈ］＋；９３．６％純度． (S)-3-(1-Hydroxypropan-2-yl)-6-morpholin-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (43) Preparation

(S)-6-chloro-3-(1-hydroxypropan-2-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidine-4(3H)- in a sealed tube On (11, 0.060 g, 0.19 mmol), potassium carbonate (0.011 g, 0.76 mmol) was added dimethylformamide (2.0 ml) followed by morpholine (0.038 g, 0.38 mmol). added. The resulting mixture was stirred at 120°C. After 24 hours, additional morpholine (38.1 mg, 0.38 mmol) was added and stirring continued at 120° C. for a further 24 hours. The reaction mixture was allowed to cool to room temperature and then partitioned between water and ethyl acetate. The organic layer was separated, dried over sodium sulfate and concentrated. Purification of the residue by silica gel chromatography using methanol/dichloromethane gave the title compound (0.026 g, 0.071 mmol, 37% yield). ¹ H NMR (DMSO-d ₆ , 400 MHz): δ 1.38 (3H, d, J = 7.04 Hz), 3.58-3.65 (5H, m), 3.76 (5H, t, J = 4.80 Hz), 4.82-4.87 (1H, m), 7.30 (1H, s); 5.03 (1H, s), 7.52 (1H, dd, J = 7.96 4.81 Hz), 8.23 (1 H, s), 8.46 (1 H, dt, J = 7.97; 1.97 Hz), 8.63 (1 H, dd, J = 4.79; 1. 75 Hz), 9.26 (1H, d, J=2.11 Hz); MS (m/z): 368.2 [M+H]+; 93.6% purity.

The compounds listed in Table 6 below were prepared following methods analogous to 43 immediately above.

再密封可能なシュレンク管、スクリューキャップ試験管に、ＣｕＩ（４ｍｇ、０．０２ｍｍｏｌ）、イミダゾール（２５ｍｇ、０．３７ｍｍｏｌ）、炭酸セシウム（２５０ｍｇ、０．７７ｍｍｏｌ）、及び撹拌子を加えた。管を脱気してから、（Ｓ）－６，８－ジクロロ－３－（１－ヒドロキシプロパン－２－イル）ピリド［３，４－ｄ］ピリミジン－４（３Ｈ）－オン（１００ｍｇ、０．３７ｍｍｏｌ）、１，１０－フェナントロリン（７ｍｇ、０．０４ｍｍｏｌ）、及び無水ジオキサン（２ｍＬ）を、アルゴン流の下で加えた。反応管を脱気し、アルゴンにより再び満たしてから、９０℃で２４時間撹拌した。反応混合物を室温に放冷した。溶液を酢酸エチル（２～３ｍＬ）により希釈し、Ｃｅｌｉｔｅのプラグに通して濾過し、追加の酢酸エチル（１０～２０ｍＬ）により溶出させた。濾液を、水、ブラインで洗浄し、Ｎａ_２ＳＯ_４で乾燥させ、濃縮した。生じた残渣をシリカゲルカラムクロマトグラフィー（ＣＨ_２Ｃｌ_２／ＭｅＯＨ）により精製すると、標記化合物を与えた（Ｃ２３、２０ｍｇ、０．０６ｍｍｏｌ、収率１８％）。^１Ｈ ＮＭＲ（ＣＨＣｌ_３－ｄ_３ ｗｉｔｈ １０％ ＣＨ_３ＯＨ－ｄ_４，４００ＭＨｚ）：δＨ １．４６（３Ｈ，ｄｄ，Ｊ＝１６．４，７．１Ｈｚ），３．８１（２Ｈ，ｓ），４．９４（１Ｈ，ｓ），５．２４（１Ｈ，ｓ），７．９４（１Ｈ，ｓ），８．３１（１Ｈ，ｓ）；ＭＳ（ｍ／ｚ）：３０６．１ ［Ｍ＋Ｈ］＋．イミダゾールプロトンは、恐らくは銅との錯化により観察されなかった。 (S)-3-(1-hydroxypropan-2-yl)-8-(1H-imidazol-1-yl)-6-(4-(trifluoromethoxy)-phenyl)pyrido[3,4-d] Preparation of pyrimidin-4(3H)-one (44):
Step 1. (S)-6-chloro-3-(1-hydroxypropan-2-yl)-8-(1H-imidazol-1-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (C23 ) preparation:

To a resealable Schlenk tube, screw cap test tube was added CuI (4 mg, 0.02 mmol), imidazole (25 mg, 0.37 mmol), cesium carbonate (250 mg, 0.77 mmol), and a stir bar. The tube was degassed before (S)-6,8-dichloro-3-(1-hydroxypropan-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (100 mg, 0 .37 mmol), 1,10-phenanthroline (7 mg, 0.04 mmol), and anhydrous dioxane (2 mL) were added under a stream of argon. The reaction tube was evacuated and refilled with argon, then stirred at 90° C. for 24 hours. The reaction mixture was allowed to cool to room temperature. The solution was diluted with ethyl acetate (2-3 mL), filtered through a plug of Celite and eluted with additional ethyl acetate (10-20 mL). The filtrate was washed with water, _brine , dried over _Na2SO4 and concentrated. The resulting residue was purified by silica gel column chromatography (CH ₂ Cl ₂ /MeOH) to give the title compound (C23, 20 mg, 0.06 mmol, 18% yield). ¹ H NMR (CHCl ₃ -d ₃ with 10% CH ₃ OH-d ₄ , 400 MHz): δH 1.46 (3H, dd, J=16.4, 7.1 Hz), 3.81 (2H, s) , 4.94 (1 H, s), 5.24 (1 H, s), 7.94 (1 H, s), 8.31 (1 H, s); MS (m/z): 306.1 [M+H] +. No imidazole protons were observed, presumably due to complexation with copper.

（Ｓ）－６－クロロ－３－（１－ヒドロキシプロパン－２－イル）－８－（１Ｈ－イミダゾール－１－イル）ピリド［３，４－ｄ］ピリミジン－４（３Ｈ）－オン（Ｃ２３、３０ｍｇ、０．１ｍｍｏｌ）及び（４－（トリフルオロメトキシ）フェニル）ボロン酸（３０ｍｇ、０．１５ｍｍｏｌ）を、１ｍＬのトルエン－ＥｔＯＨ（２：１）に溶解させ、炭酸ナトリウム（４２ｍｇ、０．４ｍｍｏｌ）を加えた。懸濁液を脱気し、アルゴンにより再び満たした（３サイクル）。テトラキス（トリフェニルホスフィン）パラジウム（１２ｍｇ、０．０１ｍｍｏｌ）を加え、懸濁液を脱気し、アルゴンにより再び満たした（３サイクル）。反応混合物を、８５℃で、アルゴン下で一晩撹拌した。反応混合物を室温に放冷し、酢酸エチルにより希釈した。溶液を、水、ブラインで洗浄し、Ｎａ_２ＳＯ_４で乾燥させ、濃縮した。残渣を、シリカゲルカラムクロマトグラフィー（ＣＨ_２Ｃｌ_２／ＭｅＯＨ）により、それに続いてＣ１８カラムにより精製すると、（Ｓ）－３－（１－ヒドロキシプロパン－２－イル）－８－（１Ｈ－イミダゾール－１－イル）－６－（４－（トリフルオロメトキシ）フェニル）ピリド［３，４－ｄ］ピリミジン－４（３Ｈ）－オンのＴＦＡ塩を与え、それを飽和Ｎａ２ＣＯ３で洗浄して、標記化合物４４の遊離塩基を与えた（１１ｍｇ、０．０２６ｍｍｏｌ、収率２６％）。^１Ｈ ＮＭＲ（ＣＨ_３ＯＨ－ｄ_４，４００ＭＨｚ）：δ １．５６（３Ｈ，ｄ，Ｊ＝７．１Ｈｚ），３．８６（１Ｈ，ｄｄ，Ｊ＝１１．９，４．３Ｈｚ），３．９７（１Ｈ，ｄｄ，Ｊ＝１１．９，６．９Ｈｚ），５．０２－４．９７（１Ｈ，ｍ），７．１６（１Ｈ，ｓ），７．４２（２Ｈ，ｄ，Ｊ＝８．４Ｈｚ），８．２８（２Ｈ，ｄ，Ｊ＝８．７Ｈｚ），８．３６（１Ｈ，ｓ），８．５０（２Ｈ，ｓ），９．１４（１Ｈ，ｓ）；ＭＳ（ｍ／ｚ）：４３２．２［Ｍ＋Ｈ］^＋；純度９８％． Step 2. (S)-3-(1-hydroxypropan-2-yl)-8-(1H-imidazol-1-yl)-6-(4-(trifluoromethoxy)phenyl)pyrido[3,4-d]pyrimidine Preparation of -4(3H)-one (44):

(S)-6-chloro-3-(1-hydroxypropan-2-yl)-8-(1H-imidazol-1-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (C23 , 30 mg, 0.1 mmol) and (4-(trifluoromethoxy)phenyl)boronic acid (30 mg, 0.15 mmol) were dissolved in 1 mL of toluene-EtOH (2:1) and sodium carbonate (42 mg, 0.1 mmol) was added. 4 mmol) was added. The suspension was degassed and refilled with argon (3 cycles). Tetrakis(triphenylphosphine)palladium (12 mg, 0.01 mmol) was added and the suspension was degassed and refilled with argon (3 cycles). The reaction mixture was stirred at 85° C. under argon overnight. The reaction mixture was allowed to cool to room temperature and diluted with ethyl acetate. The solution was washed with water, _brine , dried over _Na2SO4 and concentrated. The residue is purified by silica gel column chromatography (CH ₂ Cl ₂ /MeOH) followed by C18 column to give (S)-3-(1-hydroxypropan-2-yl)-8-(1H-imidazole- To give the TFA salt of 1-yl)-6-(4-(trifluoromethoxy)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one, which is washed with saturated Na2CO3 to give the title compound It gave the free base of 44 (11 mg, 0.026 mmol, 26% yield). ¹ H NMR (CH ₃ OH-d ₄ , 400 MHz): δ 1.56 (3H, d, J=7.1 Hz), 3.86 (1H, dd, J=11.9, 4.3 Hz), 3 .97 (1H, dd, J = 11.9, 6.9Hz), 5.02-4.97 (1H, m), 7.16 (1H, s), 7.42 (2H, d, J = MS (m /z): 432.2 [M+H] ⁺ ; purity 98%.

（Ｓ）－３－（１－ヒドロキシプロパン－２－イル）－８－（ピリジン－３－イル）－６－（ｐ－トリル）ピリド［３，４－ｄ］ピリミジン－４（３Ｈ）－オン（１７、２０ｍｇ、０．０５ｍｍｏｌ）を無水のＴＨＦに溶解させ、生じた溶液を氷水浴により冷却した。次いで、ｔ－ＢｕＯＫ（６ｍｇ、０．０５ｍｍｏｌ）を加え、それに続いてＣＨ_３Ｉ（８ｍｇ、０．０５ｍｍｏｌ）を加えた。反応混合物を１時間０℃で撹拌した。反応物を、メタノールの添加によりクエンチし、ＥｔＯＡｃで希釈した。この溶液を水、ブラインで洗浄し、Ｎａ_２ＳＯ_４で乾燥させ、濃縮し、ＨＰＬＣにより精製すると、（Ｓ）－３－（１－メトキシプロパン－２－イル）－８－（ピリジン－３－イル）－６－（ｐ－トリル）ピリド［３，４－ｄ］ピリミジン－４（３Ｈ）－オンのＴＦＡ塩を与え、それを飽和Ｎａ_２ＣＯ_３水溶液により洗浄すると、標記化合物４５の遊離塩基を与えた（２ｍｇ、０．００５ｍｍｏｌ、収率１０％）。^１Ｈ ＮＭＲ（ＣＨ_３ＯＨ－ｄ_４，４００ＭＨｚ）：δ １．５５（３Ｈ，ｄ，Ｊ＝７．１Ｈｚ），２．４１（３Ｈ，ｓ），３．３６（３Ｈ，ｓ），３．６８（１Ｈ，ｄｄ，Ｊ＝１０．５，４．２Ｈｚ），３．８５（１Ｈ，ｄｄ，Ｊ＝１０．４，７．２Ｈｚ），５．１４（１Ｈ，ｄ，Ｊ＝７．３Ｈｚ），７．３３（２Ｈ，ｄ，Ｊ＝７．９Ｈｚ），７．５９（１Ｈ，ｄｄ，Ｊ＝８．０，４．９Ｈｚ），８．０９（２Ｈ，ｄ，Ｊ＝８．０Ｈｚ），８．３９（１Ｈ，ｓ），８．５０（１Ｈ，ｓ），８．６１（１Ｈ，ｓ），８．７０（１Ｈ，ｄ，Ｊ＝８．０Ｈｚ），９．３９（１Ｈ，ｓ）；ＭＳ（ｍ／ｚ）：３８７．１ ［Ｍ＋Ｈ］＋；純度９７％． (S)-3-(1-methoxypropan-2-yl)-8-(pyridin-3-yl)-6-(p-tolyl)pyrido[3,4-d]pyrimidin-4(3H)-one Preparation of (45)

(S)-3-(1-hydroxypropan-2-yl)-8-(pyridin-3-yl)-6-(p-tolyl)pyrido[3,4-d]pyrimidin-4(3H)-one (17, 20 mg, 0.05 mmol) was dissolved in anhydrous THF and the resulting solution was cooled with an ice-water bath. t-BuOK (6 mg, 0.05 mmol) was then added followed by CH ₃ I (8 mg, 0.05 mmol). The reaction mixture was stirred for 1 hour at 0°C. The reaction was quenched by the addition of methanol and diluted with EtOAc. The solution is washed with water, brine, dried over Na ₂ SO ₄ , concentrated and purified by HPLC to give (S)-3-(1-methoxypropan-2-yl)-8-(pyridine-3- yl)-6-(p-tolyl)pyrido[3,4-d]pyrimidin-4(3H)-one to give the TFA salt, which is washed with saturated aqueous Na ₂ CO ₃ to give the free base of the title compound 45 (2 mg, 0.005 mmol, 10% yield). ¹ H NMR (CH ₃ OH-d ₄ , 400 MHz): δ 1.55 (3H, d, J=7.1 Hz), 2.41 (3H, s), 3.36 (3H, s), 3. 68 (1H, dd, J = 10.5, 4.2Hz), 3.85 (1H, dd, J = 10.4, 7.2Hz), 5.14 (1H, d, J = 7.3Hz) , 7.33 (2H, d, J=7.9 Hz), 7.59 (1 H, dd, J=8.0, 4.9 Hz), 8.09 (2H, d, J=8.0 Hz), 8.39 (1H, s), 8.50 (1H, s), 8.61 (1H, s), 8.70 (1H, d, J = 8.0 Hz), 9.39 (1H, s) MS (m/z): 387.1 [M+H]+; purity 97%.

（Ｓ）－６－クロロ－３－（１－ヒドロキシプロパン－２－イル）－８－（ピリジン－３－イル）ピリド［３，４－ｄ］ピリミジン－４（３Ｈ）－オン（１１、５０ｍｇ、０．１５ｍｍｏｌ）をトルエンに溶解させた。溶液を脱気してから、Ｐｄ（ｄｐｐｆ）Ｃｌ_２・ＣＨ_２Ｃｌ_２（１３ｍｇ、０．０１６ｍｍｏｌ）、ＬｉＣｌ（２６ｍｇ、４当量）、ＣｕＩ（６ｍｇ、０．０３２ｍｍｏｌ）、及び２－（トリブチルスタンニル）－５－（トリフルオロメチル）ピリジン（８３ｍｇ、０．１９ｍｍｏｌ）を加えた。溶液を再び脱気し、８０℃で一晩撹拌した。反応混合物のＬＣＭＳモニタリングは、予測される生成物への不完全な転化を示したので、３０ｍｇのＣｕＩを加え、反応をさらに６時間８０℃で進行させた。反応混合物を室温に放冷し、それをＥｔＯＡｃで希釈した。この溶液を水、ブラインで洗浄し、Ｎａ_２ＳＯ_４で乾燥させた。溶媒を減圧下で除去し、残渣を、シリカゲルカラムクロマトグラフィー（ＣＨ_２Ｃｌ_２／ＭｅＯＨ）により、それに続いてＣ１８カラムクロマトグラフィーにより精製すると、（Ｓ）－３－（１－ヒドロキシプロパン－２－イル）－８－（ピリジン－３－イル）－６－（５－（トリフルオロメチル）ピリジン－２－イル）ピリド［３，４－ｄ］ピリミジン－４（３Ｈ）－オンのＴＦＡ塩を与え、それを飽和Ｎａ_２ＣＯ_３水溶液で洗浄すると、標記化合物の遊離塩基を与えた（８ｍｇ、０．０１９ｍｍｏｌ、収率１２％）。^１Ｈ ＮＭＲ（ＣＨ_３ＯＨ－ｄ_４，４００ＭＨｚ）：δ １．５６（３Ｈ，ｄ，Ｊ＝７．１Ｈｚ），３．８５（１Ｈ，ｄｄ，Ｊ＝１１．９，４．３Ｈｚ），３．９６（１Ｈ，ｄｄ，Ｊ＝１１．９，６．９Ｈｚ），５．０１－４．９６（１Ｈ，ｍ），７．６０（１Ｈ，ｄｄ，Ｊ＝８．０，４．９Ｈｚ），８．２４（１Ｈ，ｄ，Ｊ＝８．５Ｈｚ），８．４６（１Ｈ，ｓ），８．６３（１Ｈ，ｄ，Ｊ＝４．９Ｈｚ），８．７４－８．７０（２Ｈ，ｍ），８．９９（１Ｈ，ｓ），９．１３（１Ｈ，ｓ），９．４１（１Ｈ，ｓ）；ＭＳ（ｍ／ｚ）：４２８．１ ［Ｍ＋Ｈ］＋；純度９９％． (S)-3-(1-hydroxypropan-2-yl)-8-(pyridin-3-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido [3,4-d ] Preparation of pyrimidin-4(3H)-one (46)

(S)-6-chloro-3-(1-hydroxypropan-2-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (11, 50 mg , 0.15 mmol) was dissolved in toluene. The solution was degassed before adding Pd(dppf)Cl ₂ .CH ₂ Cl ₂ (13 mg, 0.016 mmol), LiCl (26 mg, 4 eq), CuI (6 mg, 0.032 mmol), and 2-(tributylstane). Nyl)-5-(trifluoromethyl)pyridine (83 mg, 0.19 mmol) was added. The solution was degassed again and stirred at 80° C. overnight. LCMS monitoring of the reaction mixture indicated incomplete conversion to the expected product, so 30 mg of CuI was added and the reaction was allowed to proceed at 80° C. for an additional 6 hours. The reaction mixture was allowed to cool to room temperature and it was diluted with EtOAc. The solution was washed with water, _brine and dried over _Na2SO4 . The solvent is removed under reduced pressure and the residue is purified by silica gel column chromatography (CH ₂ Cl ₂ /MeOH) followed by C18 column chromatography to give (S)-3-(1-hydroxypropane-2- to give the TFA salt of yl)-8-(pyridin-3-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one , which was washed with saturated aqueous Na ₂ CO ₃ gave the free base of the title compound (8 mg, 0.019 mmol, 12% yield). ¹ H NMR (CH ₃ OH-d ₄ , 400 MHz): δ 1.56 (3H, d, J=7.1 Hz), 3.85 (1H, dd, J=11.9, 4.3 Hz), 3 .96 (1H, dd, J = 11.9, 6.9Hz), 5.01-4.96 (1H, m), 7.60 (1H, dd, J = 8.0, 4.9Hz), 8.24 (1H, d, J = 8.5Hz), 8.46 (1H, s), 8.63 (1H, d, J = 4.9Hz), 8.74-8.70 (2H, m ), 8.99 (1H, s), 9.13 (1H, s), 9.41 (1H, s); MS (m/z): 428.1 [M+H]+; purity 99%.

（Ｓ）－６－クロロ－８－（３－フルオロフェニル）－３－（１－ヒドロキシプロパン－２－イル）ピリド［３，４－ｄ］ピリミジン－４（３Ｈ）－オン（Ｃ１、５０ｍｇ、０．１５ｍｍｏｌ）をトルエンに溶解させ、脱気してから、Ｐｄ（ｄｐｐｆ）Ｃｌ_２・ＣＨ_２Ｃｌ_２（２４ｍｇ、０．１８ｍｇ）、ＬｉＣｌ（２６ｍｇ、０．６ｍｍｏｌ）、ＣｕＩ（２９ｍｇ、０．１５ｍｍｏｌ）、及び２－（トリブチルスタンニル）－５－（トリフルオロメチル）ピリジン（７９ｍｇ、０．１８ｍｍｏｌ）を加えた。溶液を再び脱気し、８０℃で一晩撹拌した。反応混合物をＥｔＯＡｃで希釈し、水、ブラインで洗浄し、Ｎａ_２ＳＯ_４で乾燥させた。溶媒を真空下で除去し、残渣を、シリカゲルカラムクロマトグラフィー（ＣＨ_２Ｃｌ_２／ＭｅＯＨ）により、それに続いてＣ１８カラムにより精製すると、（Ｓ）－８－（３－フルオロフェニル）－３－（１－ヒドロキシプロパン－２－イル）－６－（５－（トリフルオロメチル）ピリジン－２－イル）ピリド［３，４－ｄ］ピリミジン－４（３Ｈ）－オンのＴＦＡ塩を与え、それを飽和Ｎａ_２ＣＯ_３で洗浄すると、標記化合物の遊離塩基を与えた（１９ｍｇ、０．０４ｍｍｏｌ、収率２５％）。^１Ｈ ＮＭＲ（ＣＨ_３ＯＨ－ｄ_４，４００ＭＨｚ）：δＨ １．５６（３Ｈ，ｄ，Ｊ＝７．１Ｈｚ），３．８５（１Ｈ，ｄｄ，Ｊ＝１１．９，４．３Ｈｚ），３．９６（１Ｈ，ｄｄ，Ｊ＝１１．９，６．９Ｈｚ），５．０１－４．９６（１Ｈ，ｍ），７．６０（１Ｈ，ｄｄ，Ｊ＝８．０，４．９Ｈｚ），８．２４（１Ｈ，ｄ，Ｊ＝８．５Ｈｚ），８．４６（１Ｈ，ｓ），８．６３（１Ｈ，ｄ，Ｊ＝４．９Ｈｚ），８．７４－８．７０（２Ｈ，ｍ），８．９９（１Ｈ，ｓ），９．１３（１Ｈ，ｓ），９．４１（１Ｈ，ｓ）．；ＭＳ（ｍ／ｚ）：４４５．１ ［Ｍ＋Ｈ］＋；純度９９％． (S)-8-(3-fluorophenyl)-3-(1-hydroxypropan-2-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d] Preparation of pyrimidin-4(3H)-one (47):

(S)-6-chloro-8-(3-fluorophenyl)-3-(1-hydroxypropan-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (C1, 50 mg, 0.15 mmol) was dissolved in toluene and degassed before adding Pd ₍ dppf) _{Cl2.CH2Cl2 (} 24 mg, 0.18 mg), LiCl (26 mg, 0.6 mmol), CuI (29 mg, 0.6 mmol). 15 mmol), and 2-(tributylstannyl)-5-(trifluoromethyl)pyridine (79 mg, 0.18 mmol) were added. The solution was degassed again and stirred at 80° C. overnight. The reaction mixture was diluted with EtOAc, washed with water, _brine and dried over _Na2SO4 . The solvent is removed under vacuum and the residue is purified by silica gel column chromatography (CH ₂ Cl ₂ /MeOH) followed by C18 column to give (S)-8-(3-fluorophenyl)-3-( to give the TFA salt of 1-hydroxypropan-2-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one, which Washing with saturated Na ₂ CO ₃ gave the free base of the title compound (19 mg, 0.04 mmol, 25% yield). ¹ H NMR (CH ₃ OH-d ₄ , 400 MHz): δH 1.56 (3H, d, J=7.1 Hz), 3.85 (1H, dd, J=11.9, 4.3 Hz), 3 .96 (1H, dd, J = 11.9, 6.9Hz), 5.01-4.96 (1H, m), 7.60 (1H, dd, J = 8.0, 4.9Hz), 8.24 (1H, d, J = 8.5Hz), 8.46 (1H, s), 8.63 (1H, d, J = 4.9Hz), 8.74-8.70 (2H, m ), 8.99 (1 H, s), 9.13 (1 H, s), 9.41 (1 H, s). MS (m/z): 445.1 [M+H]+; purity 99%.

Compounds prepared in a similar manner to 47 are listed in Table 7 below.

ＭｅＯＨ（２５ｍＬ）及びＥｔＯＡｃ（２５ｍＬ）中の３－［（１Ｓ）－２－ベンジルオキシ－１－メチル－エチル］－８－（３－フルオロフェニル）－６－（ｐ－トリル）ピリド［３，４－ｄ］ピリミジン－４－オン（４０、１６０ｍｇ、３３３．６５ｕｍｏｌ、１当量）及びＰｄ／Ｃ（８０ｍｇ、３３３．６５ｕｍｏｌ、純度１０％、１．００当量）の混合物を脱気し、Ｈ_２（１５ｐｓｉ）により３回置換し、次いで混合物を８０℃で１５時間Ｈ_２雰囲気下で撹拌した。ＬＣＭＳは、所望の化合物を検出したことを示した。反応混合物を濾過し、濾液を減圧下で濃縮すると残渣を与えた。残渣を分取ＴＬＣ（ＳｉＯ_２、石油エーテル／酢酸エチル＝１：１）により精製すると、標記化合物を得た（４７ｍｇ、１２０．６９ｕｍｏｌ、収率３６．１７％）。^１Ｈ ＮＭＲ（４００ＭＨｚ，ＤＭＳＯ－ｄ_６）δ ｐｐｍ １．４３（ｄ，Ｊ＝６．８Ｈｚ，３Ｈ），２．３９（ｓ，３Ｈ），３．６２－３．７１（ｍ，１Ｈ），３．７６－３．８４（ｍ，１Ｈ），４．８４－４．９６（ｍ，１Ｈ），５．０７（ｔ，Ｊ＝５．６Ｈｚ，１Ｈ），７．３３－７．３７（ｍ，３Ｈ），７．５９（ｑ，Ｊ＝７．６，１４．０Ｈｚ，１Ｈ），８．０３－８．０９（ｍ，２Ｈ），８．１６（ｄ，Ｊ＝８．４Ｈｚ，２Ｈ），８．４６（ｓ，１Ｈ），８．５３（ｓ，１Ｈ）；ＭＳ：Ｍ＋Ｈ＋，３９０．１；９８％純度． 8-(3-fluorophenyl)-3-[(1S)-2-hydroxy-1-methyl-ethyl]-6-(p-tolyl)pyrido[3,4-d]pyrimidin-4-one (48) preparation of

3-[(1S)-2-benzyloxy-1-methyl-ethyl]-8-(3-fluorophenyl)-6-(p-tolyl)pyrido[3,5 in MeOH (25 mL) and EtOAc (25 mL). A mixture of 4-d]pyrimidin-4-one (40, 160 mg, 333.65 umol, 1 eq) and Pd/C (80 mg, 333.65 umol, 10% purity, 1.00 eq) is degassed and treated with H ₂ (15 psi) three times, then the mixture was stirred at 80° C. for 15 hours under H ₂ atmosphere. LCMS indicated detection of the desired compound. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC (SiO ₂ , petroleum ether/ethyl acetate=1:1) to give the title compound (47 mg, 120.69 umol, 36.17% yield). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.43 (d, J = 6.8 Hz, 3H), 2.39 (s, 3H), 3.62-3.71 (m, 1H), 3.76-3.84 (m, 1H), 4.84-4.96 (m, 1H), 5.07 (t, J=5.6Hz, 1H), 7.33-7.37 (m , 3H), 7.59 (q, J = 7.6, 14.0Hz, 1H), 8.03-8.09 (m, 2H), 8.16 (d, J = 8.4Hz, 2H) , 8.46 (s, 1H), 8.53 (s, 1H); MS: M+H+, 390.1; 98% purity.

３－［（１Ｓ）－２－ベンジルオキシ－１－メチル－エチル］－６－クロロ－８－（３－フルオロフェニル）ピリド［３，４－ｄ］ピリミジン－４－オン（Ｃ２１、４６０ｍｇ、１．０９ｍｍｏｌ、１当量）及び［４－（トリフルオロメトキシ）フェニル］ボロン酸（２６８．１８ｍｇ、１．３０ｍｍｏｌ、１．２当量）のトルエン（８ｍＬ）及びＥｔＯＨ（４ｍＬ）中の溶液に、Ｎａ_２ＣＯ_３（４６０．１０ｍｇ、４．３４ｍｍｏｌ、４当量）及びＰｄ（ＰＰｈ_３）_４（１２５．４１ｍｇ、１０８．５２ｕｍｏｌ、０．１当量）を加えた。混合物をマイクロ波チューブに詰めた（ｔａｋｅｎ ｕｐ ｉｎｔｏ）。密封したチューブを、１００℃で１時間マイクロ波の下で加熱した。ＬＣＭＳは、所望の化合物が検出されたことを示した。反応混合物を濾過し、濾液を減圧下で濃縮すると、残渣を与えた。残渣をカラムクロマトグラフィー（ＳｉＯ_２、石油エーテル／酢酸エチル＝１／０～０／１）により精製すると、標記化合物を得た（４００ｍｇ、７２７．９２ｕｍｏｌ、収率６７．０７％）。ＭＳ：Ｍ＋Ｈ＋、５５０．１。 8-(3-fluorophenyl)-3-[(1S)-2-hydroxy-1-methyl-ethyl]-6-[4-(trifluoromethoxy)phenyl]pyrido[3,4-d]pyrimidine-4 1.3-[(1S)-2-Benzyloxy-1-methyl-ethyl]-8-(3-fluorophenyl)-6-[4-(trifluoromethoxy)phenyl] Preparation of pyrido[3,4-d]pyrimidin-4-one (precursor 1)

3-[(1S)-2-benzyloxy-1-methyl-ethyl]-6-chloro-8-(3-fluorophenyl)pyrido[3,4-d]pyrimidin-4-one (C21, 460 mg, 1 To a solution of [4-(trifluoromethoxy)phenyl]boronic acid (268.18 mg, 1.30 mmol, 1.2 eq) in toluene (8 mL) and EtOH (4 mL) was added Na _{2 CO3} (460.10 mg, 4.34 mmol, _{4 eq) and Pd(PPh3)4 (} 125.41 mg, 108.52 umol, 0.1 eq) were added. The mixture was taken up into microwave tubes. The sealed tube was heated under microwave at 100° C. for 1 hour. LCMS indicated the desired compound was detected. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=1/0 to 0/1) to give the title compound (400 mg, 727.92 umol, 67.07% yield). MS: M+H+, 550.1.

３－［（１Ｓ）－２－ベンジルオキシ－１－メチル－エチル］－８－（３－フルオロフェニル）－６－［４－（トリフルオロメトキシ）フェニル］ピリド［３，４－ｄ］ピリミジン－４－オン（前駆体１、２９０ｍｇ、５２７．７４ｕｍｏｌ、１当量）のＥｔＯＡｃ（２０ｍＬ）及びＭｅＯＨ（２０ｍＬ）中の溶液に、Ｐｄ（ＯＨ）_２／Ｃ（１３０ｍｇ、５２７．７４ｕｍｏｌ、純度１０％、１．００当量）を加えた。混合物を、２５℃で６時間、Ｈ_２下で（１５ｐｓｉ）撹拌した。ＬＣＭＳは、所望の質量が検出されたことを示した。反応混合物を濾過し、濾液を減圧下で濃縮すると、残渣を与えた。残渣を、分取ＴＬＣ（ＳｉＯ_２、石油エーテル／酢酸エチル＝１：１）により精製すると、標記化合物４９を得た（２２ｍｇ、４７．４１ｕｍｏｌ、収率８．９８％）、^１Ｈ ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ ｐｐｍ １．６１（ｄ，Ｊ＝７．１Ｈｚ，３Ｈ），１．９４－２．０５（ｍ，１Ｈ），３．９５－４．０４（ｍ，２Ｈ），５．０４－５．１５（ｍ，１Ｈ），７．１７－７．２５（ｍ，１Ｈ），７．３６（ｄ，Ｊ＝８．４Ｈｚ，２Ｈ），７．４６－７．５４（ｍ，１Ｈ），７．９４－８．０７（ｍ，２Ｈ），８．２６（ｄ，Ｊ＝８．４Ｈｚ，２Ｈ），８．３２（ｓ，１Ｈ），８．５３（ｓ，１Ｈ）．ＭＳ：Ｍ＋Ｈ＋，４６０．１；９９％純度． Step 2. 8-(3-Fluorophenyl)-3-[(1S)-2-hydroxy-1-methyl-ethyl]-6-[4-(trifluoromethoxy)phenyl]pyrido[3,4-d] Preparation of pyrimidin-4-ones (49)

3-[(1S)-2-benzyloxy-1-methyl-ethyl]-8-(3-fluorophenyl)-6-[4-(trifluoromethoxy)phenyl]pyrido[3,4-d]pyrimidine- To a solution of 4-one (precursor 1, 290 mg, 527.74 umol, 1 eq) in EtOAc (20 mL) and MeOH (20 mL) was added Pd(OH) ₂ /C (130 mg, 527.74 umol, purity 10%, 1.00 eq.) was added. The mixture was stirred under H ₂ (15 psi) at 25° C. for 6 hours. LCMS indicated the desired mass was detected. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC (SiO ₂ , petroleum ether/ethyl acetate=1:1) to give the title compound 49 (22 mg, 47.41 umol, 8.98% yield), ¹ H NMR (400 MHz , CDCl ₃ ) δ ppm 1.61 (d, J = 7.1 Hz, 3H), 1.94-2.05 (m, 1H), 3.95-4.04 (m, 2H), 5.04 -5.15 (m, 1H), 7.17-7.25 (m, 1H), 7.36 (d, J=8.4Hz, 2H), 7.46-7.54 (m, 1H) , 7.94-8.07 (m, 2H), 8.26 (d, J=8.4 Hz, 2H), 8.32 (s, 1H), 8.53 (s, 1H). MS: M+H+, 460.1; 99% pure.

Compounds encompassed within this disclosure can be prepared by the procedures outlined in Scheme II and described in the Examples below.

前駆体２を、１の合成の工程３に関して報告された手順に従って調製した。^１Ｈ ＮＭＲ（ＣＨＣｌ_３－ｄ，４００ＭＨｚ）：δ_Ｈ ３．９５（３Ｈ，ｓ），５．９１（２Ｈ，ｓ），７．４４（１Ｈ，ｄｄ，Ｊ＝７．９，４．９Ｈｚ），７．７４（１Ｈ，ｓ），７．９７（１Ｈ，ｄ，Ｊ＝７．９Ｈｚ），８．６９（１Ｈ，ｄｄ，Ｊ＝４．９，１．７Ｈｚ），８．９１（１Ｈ，ｓ）；ＭＳ（ｍ／ｚ）：２６４．０ ［Ｍ＋Ｈ］^＋． 3-(1,1-dioxidotetrahydrothiophen-3-yl)-8-(pyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido [3,4-d ] Pyrimidin-4(3H)-one (106) preparation step 1. Preparation of methyl 3-amino-6-chloro-[2,3′-bipyridine]-4-carboxylate (precursor 2):

Precursor 2 was prepared following the procedure reported for step 3 of the synthesis of 1. ¹ H NMR (CHCl ₃ -d, 400 MHz): δ _H 3.95 (3H, s), 5.91 (2H, s), 7.44 (1H, dd, J=7.9, 4.9 Hz) , 7.74 (1H, s), 7.97 (1H, d, J = 7.9 Hz), 8.69 (1H, dd, J = 4.9, 1.7 Hz), 8.91 (1H, s); MS (m/z): 264.0 [M+H] ⁺ .

Table 8 lists intermediates prepared by procedures similar to those described in Step 1 above.

前駆体３を、１の合成の工程３に関して報告された手順に従って調製した。^１Ｈ ＮＭＲ（ＣＨＣｌ_３－ｄ，４００ＭＨｚ）：δ_Ｈ ４．０１（３Ｈ，ｓ），６．２０（２Ｈ，ｓ），７．４９（１Ｈ，ｔ，Ｊ＝６．４Ｈｚ），７．７３（１Ｈ，ｄ，Ｊ＝８．２Ｈｚ），８．０６（１Ｈ，ｄ，Ｊ＝７．９Ｈｚ），８．２５（１Ｈ，ｓ），８．４６（１Ｈ，ｄ，Ｊ＝８．３Ｈｚ），８．７４（１Ｈ，ｄ，Ｊ＝４．９Ｈｚ），９．００（１Ｈ，ｓ），９．２７（１Ｈ，ｓ）；ＭＳ（ｍ／ｚ）：３７５．０［Ｍ＋Ｈ］^＋． Step 2. Preparation of methyl 3′-amino-6″-(trifluoromethyl)-[3,2′:6′,3″-terpyridine]-4′-carboxylate (precursor 3):

Precursor 3 was prepared following the procedure reported for step 3 of the synthesis of 1. ¹ H NMR (CHCl ₃ -d, 400 MHz): δ _H 4.01 (3H, s), 6.20 (2H, s), 7.49 (1H, t, J=6.4 Hz), 7.73 (1H, d, J = 8.2Hz), 8.06 (1H, d, J = 7.9Hz), 8.25 (1H, s), 8.46 (1H, d, J = 8.3Hz) , 8.74 (1 H, d, J=4.9 Hz), 9.00 (1 H, s), 9.27 (1 H, s); MS (m/z): 375.0 [M+H] ⁺ .

Table 9 lists intermediates prepared by procedures analogous to those described above.

メチル３’－アミノ－６’’－（トリフルオロメチル）－［３，２’：６’，３’’－テルピリジン］－４’－カルボキシレート（前駆体３、３．５ｇ、８．３２ｍｍｏｌ）のＴＨＦ：水（４２ｍＬ：１４ｍＬ）中の溶液を０℃に冷却し；ＬｉＯＨ（１．０５ｇ、２４．９６ｍｍｏｌ）を加えた。反応物を０℃で１時間撹拌し、室温で一晩撹拌した。反応混合物をＡｍｂｅｒｌｉｔｅ ＩＲ１２０によりｐＨ４に酸性化し、それに続いて酢酸エチル及びＭｅＯＨを加えた。溶液を濾過して樹脂を除去し、溶媒を蒸発させると、３’－アミノ－６’’－（トリフルオロメチル）－［３，２’：６’，３’’－テルピリジン］－４’－カルボン酸を与えた（３．０ｇ、７．９１ｍｍｏｌ、収率９５％、＞純度９５％）。ＭＳ（ｍ／ｚ）：３６１．１［Ｍ＋Ｈ］^＋。酸中間体を直接次の工程に付した。 Step 3. 3′-Amino-N-(1,1-dioxidotetrahydrothiophen-3-yl)-6″-(trifluoromethyl)-[3,2′:6′,3″-terpyridine] Preparation of -4'-carboxamide (precursor 4)

Methyl 3′-amino-6″-(trifluoromethyl)-[3,2′:6′,3″-terpyridine]-4′-carboxylate (precursor 3, 3.5 g, 8.32 mmol) in THF:water (42 mL:14 mL) was cooled to 0° C.; LiOH (1.05 g, 24.96 mmol) was added. The reaction was stirred at 0° C. for 1 hour and at room temperature overnight. The reaction mixture was acidified to pH 4 with Amberlite IR120 followed by addition of ethyl acetate and MeOH. The solution is filtered to remove the resin and the solvent is evaporated to give 3′-amino-6″-(trifluoromethyl)-[3,2′:6′,3″-terpyridine]-4′- It gave the carboxylic acid (3.0 g, 7.91 mmol, 95% yield, >95% purity). MS (m/z): 361.1 [M+H] ^<+ >. The acid intermediate was taken directly to the next step.

3′-amino-6″-(trifluoromethyl)-[3,2′:6′,3″-terpyridine]-4′-carboxylic acid (0.6 g, 1.67 mmol) and 3-aminotetrahydro Thiophene 1,1-dioxide. A mixture of HCl (0.314 g, 1.83 mmol) was dissolved in DMF (8.0 mL) and the reaction mixture was cooled to 0.degree. Diisopropylethylamine (0.87 mL, 4.5 mmol) and HATU (0.633 g, 1.67 mmol) were added. The reaction was stirred at 0° C. for 1 hour and at room temperature overnight. The reaction was quenched with water and partitioned between ethyl acetate and water. The organic phase was separated and washed with saturated aqueous ammonium chloride solution and then saturated aqueous sodium bicarbonate solution. The organic phase is dried over anhydrous magnesium sulfate, filtered and evaporated to give the title compound 3′-amino-N-(1,1-dioxidotetrahydrothiophen-3-yl)-6″-(trifluoromethyl) -[3,2′:6′,3″-Terpyridine]-4′-carboxamide was given (Precursor 4, 0.58 g, 66% yield, >90% purity). MS (m/z): 478.1 [M+H] ^<+ >. The crude product was taken to the next step without purification.

Table 10 lists intermediates prepared by procedures analogous to those described in the above steps.

バイアル内のメチル３’－アミノ－６’’－（トリフルオロメチル）－［３，２’：６’，３’’－テルピリジン］－４’－カルボキシレート（３００ｍｇ、０．８０１ｍｍｏｌ）に、７ＭアンモニアのＭｅＯＨ溶液を加え、密封し、６５℃で一晩加熱した。溶媒を蒸発させると、化合物Ｆ３０が白色の固体として得られ、さらに精製せずに使用した（２７０ｍｇ、８９％）。ＭＳ（ｍ／ｚ）：４８８．０［Ｍ＋Ｈ］^＋；純度９５％。 Preparation of 3′-amino-6″-(trifluoromethyl)-[3,2′:6′,3″-terpyridine]-4′-carboxamide (F30)

To methyl 3′-amino-6″-(trifluoromethyl)-[3,2′:6′,3″-terpyridine]-4′-carboxylate (300 mg, 0.801 mmol) in a vial, 7M A solution of ammonia in MeOH was added, sealed and heated at 65° C. overnight. Evaporation of the solvent gave compound F30 as a white solid, which was used without further purification (270 mg, 89%). MS (m/z): 488.0 [M+H] ⁺ ; 95% purity.

オルトギ酸トリエチル（１０ｍＬ）を、密封したチューブ内の３’－アミノ－Ｎ－（１，１－ジオキシドテトラヒドロチオフェン－３－イル）－６’’－（トリフルオロメチル）－［３，２’：６’，３’’－テルピリジン］－４’－カルボキサミド（前駆体４、０．３ｇ、０．６１８ｍｍｏｌ）に加えた。酢酸（１ｍＬ、１０％ｖ／ｖ）を室温で加え、生じた混合物を９５℃で一晩加熱した。混合物を濃縮し、それに続いて飽和ＮａＨＣＯ_３を加え、固体を真空濾過により回収し、水で洗浄し、乾燥させた。残渣を順相クロマトグラフィーにより精製すると、標記化合物３－（１，１－ジオキシドテトラヒドロチオフェン－３－イル）－８－（ピリジン－３－イル）－６－（６－（トリフルオロメチル）ピリジン－３－イル）ピリド［３，４－ｄ］ピリミジン－４（３Ｈ）－オンを与えた（１０６、０．１３ｇ、収率４３％）。^１Ｈ ＮＭＲ（ＤＭＳＯ－ｄ_６，３００ＭＨｚ）：δＨ ２．７０－２．６７（２Ｈ，ｍ），３．３７－３．３０（１Ｈ，ｍ），３．７０－３．５７（２Ｈ，ｍ），５．４２（１Ｈ，ｔ，Ｊ＝８．３Ｈｚ），７．６２（１Ｈ，ｄｄ，Ｊ＝７．９，４．８Ｈｚ），８．０７（１Ｈ，ｄ，Ｊ＝８．３Ｈｚ），８．５８（１Ｈ，ｄ，Ｊ＝８．１Ｈｚ），８．６４（１Ｈ，ｓ），８．７２（１Ｈ，ｄ，Ｊ＝４．７Ｈｚ），８．８０（１Ｈ，ｓ），８．９６（１Ｈ，ｄ，Ｊ＝８．４Ｈｚ），９．３７（１Ｈ，ｓ），９．６６（１Ｈ，ｓ）；ＭＳ（ｍ／ｚ）：４８８．０ ［Ｍ＋Ｈ］^＋；＞９８％純度． Step 4-3-(1,1-Dioxidotetrahydrothiophen-3-yl)-8-(pyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3, Preparation of 4-d]pyrimidin-4(3H)-one (106)

Triethyl orthoformate (10 mL) was added to 3′-amino-N-(1,1-dioxidotetrahydrothiophen-3-yl)-6″-(trifluoromethyl)-[3,2′ in a sealed tube. : 6′,3″-terpyridine]-4′-carboxamide (precursor 4, 0.3 g, 0.618 mmol). Acetic acid (1 mL, 10% v/v) was added at room temperature and the resulting mixture was heated at 95° C. overnight. The mixture was concentrated followed by the addition of saturated NaHCO ₃ and the solid was collected by vacuum filtration, washed with water and dried. Purification of the residue by normal phase chromatography gives the title compound 3-(1,1-dioxidotetrahydrothiophen-3-yl)-8-(pyridin-3-yl)-6-(6-(trifluoromethyl)pyridine -3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (106, 0.13 g, 43% yield). ¹ H NMR (DMSO-d ₆ , 300 MHz): δH 2.70-2.67 (2H, m), 3.37-3.30 (1H, m), 3.70-3.57 (2H, m ), 5.42 (1H, t, J = 8.3 Hz), 7.62 (1H, dd, J = 7.9, 4.8 Hz), 8.07 (1H, d, J = 8.3 Hz) , 8.58 (1 H, d, J = 8.1 Hz), 8.64 (1 H, s), 8.72 (1 H, d, J = 4.7 Hz), 8.80 (1 H, s), 8 .96 (1 H, d, J=8.4 Hz), 9.37 (1 H, s), 9.66 (1 H, s); MS (m/z): 488.0 [M+H] ⁺ ; >98% purity.

ジオキサン（７ｍＬ）及びオルトギ酸トリエチル（１．２ｍＬ、７．０２ｍｍｏｌ）を、フラスコ内の中間体（Ｒ）－３’－アミノ－Ｎ－（１，１－ジオキシドテトラヒドロチオフェン－３－イル）－６’’－（トリフルオロメチル）－［３，２’：６’，３’’－テルピリジン］－４’－カルボキサミド（Ｆ１、０．６７ｇ、１．４ｍｍｏｌ）に加えた。ｐ－トルエンスルホン酸（０．２６７ｍｇ、１．４ｍｍｏｌ）を室温で加え、生じた混合物を一晩撹拌した。混合物を濃縮し、それに続いて飽和ＮａＨＣＯ_３を加え、形成した固体を真空濾過により回収し、水で洗浄し、乾燥させた。残渣をシリカゲルカラムクロマトグラフィーにより精製すると、標記化合物（Ｒ）－３－（１，１－ジオキシドテトラヒドロチオフェン－３－イル）－８－（ピリジン－３－イル）－６－（６－（トリフルオロメチル）ピリジン－３－イル）ピリド［３，４－ｄ］ピリミジン－４（３Ｈ）－オンを与えた（９８ １．８２ｇ、収率６９％）。^１Ｈ ＮＭＲ（ＤＭＳＯ－ｄ_６，４００ＭＨｚ）：δ_Ｈ ３．２５－３．１８（２Ｈ，ｍ），３．９０－３．８７（１Ｈ，ｍ），４．２５－４．１２（３Ｈ，ｍ），５．９６（１Ｈ，ｔ，Ｊ＝８．５Ｈｚ），８．１６（１Ｈ，ｄ，Ｊ＝６．７Ｈｚ），８．６２（１Ｈ，ｄ，Ｊ＝８．３Ｈｚ），９．１１（１Ｈ，ｄ，Ｊ＝８．０Ｈｚ），９．１８（１Ｈ，ｓ），９．２７（１Ｈ，ｓ），９．３５（１Ｈ，ｓ），９．５０（１Ｈ，ｓ），９．９０（１Ｈ，ｓ），１０．２０（１Ｈ，ｓ）；ＭＳ（ｍ／ｚ）：４８８．１ ［Ｍ＋Ｈ］^＋；９９％純度 (R)-3-(1,1-dioxidotetrahydrothiophen-3-yl)-8-(pyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido [3 ,4-d]pyrimidin-4(3H)-one (107)

Dioxane (7 mL) and triethyl orthoformate (1.2 mL, 7.02 mmol) were added to the intermediate (R)-3′-amino-N-(1,1-dioxydotetrahydrothiophen-3-yl)- in a flask. 6″-(trifluoromethyl)-[3,2′:6′,3″-terpyridine]-4′-carboxamide (F1, 0.67 g, 1.4 mmol) was added. p-Toluenesulfonic acid (0.267 mg, 1.4 mmol) was added at room temperature and the resulting mixture was stirred overnight. The mixture was concentrated followed by the addition of saturated NaHCO ₃ and the solid that formed was collected by vacuum filtration, washed with water and dried. The residue was purified by silica gel column chromatography to give the title compound (R)-3-(1,1-dioxidotetrahydrothiophen-3-yl)-8-(pyridin-3-yl)-6-(6-(tri Fluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one was given (98 1.82 g, 69% yield). ¹ H NMR (DMSO-d ₆ , 400 MHz): δ _H 3.25-3.18 (2H, m), 3.90-3.87 (1H, m), 4.25-4.12 (3H, m), 5.96 (1 H, t, J = 8.5 Hz), 8.16 (1 H, d, J = 6.7 Hz), 8.62 (1 H, d, J = 8.3 Hz), 9. 11 (1H, d, J = 8.0Hz), 9.18 (1H, s), 9.27 (1H, s), 9.35 (1H, s), 9.50 (1H, s), 9 .90 (1H, s), 10.20 (1H, s); MS (m/z): 488.1 [M+H] ⁺ ; 99% purity

Table 11 lists compounds prepared by a procedure similar to that described for 98, substituting reactants 4, 5, and 6 with the groups indicated.

オルトギ酸トリエチル（１．６９ｍｌ、１０．２ｍｍｏｌ）及びｐ－トルエンスルホン酸（１１７ｍｇ、０．６７９ｍｍｏｌ）を、（Ｓ）－３’－アミノ－６’’－シクロプロピル－Ｎ－（３，３，３－トリフルオロ－２－ヒドロキシプロピル）－［３，２’：６’，３’’－テルピリジン］－４’－カルボキサミド（３０１ｍｇ、０．６７９ｍｍｏｌ）のジオキサン（３．４ｍｌ）溶液に加えた。１時間後、ＤＭＦ（０．５ｍｌ）を加え、反応混合物を４０℃に加熱し、４８時間撹拌した。反応混合物を炭酸水素ナトリウム（ｐＨ＞１１）によりクエンチした。水を加え、混合物を酢酸エチルで抽出した。合わせた有機層を無水硫酸マグネシウムで乾燥させ、濃縮し、シリカゲルカラムクロマトグラフィーにより精製すると、標記化合物（Ｓ）－６－（６－シクロプロピルピリジン－３－イル）－８－（ピリジン－３－イル）－３－（３，３，３－トリフルオロ－２－ヒドロキシプロピル）ピリド［３，４－ｄ］ピリミジン－４（３Ｈ）－オンを白色の固体として与えた（１２０、１１５ｍｇ、３７％）。^１Ｈ ＮＭＲ（ＤＭＳＯ－ｄ_６，４００ＭＨｚ）：δ １．０２（４Ｈ，ｄ，Ｊ＝８．２Ｈｚ），２．２３－２．１７（１Ｈ，ｍ），４．０８（１Ｈ，ｄｄ，Ｊ＝１４．１，９．９Ｈｚ），４．４５（２Ｈ，ｄ，Ｊ＝１２．５Ｈｚ），６．７８（１Ｈ，ｄ，Ｊ＝６．４Ｈｚ），７．４７（１Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．５９（１Ｈ，ｄｄ，Ｊ＝７．９，４．８Ｈｚ），８．４９－８．４７（２Ｈ，ｍ），８．５４（２Ｈ，ｄ，Ｊ＝１１．８Ｈｚ），８．７０（１Ｈ，ｄ，Ｊ＝４．８Ｈｚ），９．２６（１Ｈ，ｓ），９．３２（１Ｈ，ｓ）；ＭＳ（ｍ／ｚ）：４５４．２ ［Ｍ＋Ｈ］^＋；＞９９％純度． (S)-6-(6-cyclopropylpyridin-3-yl)-8-(pyridin-3-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl) as a white solid Preparation of pyrido[3,4-d]pyrimidin-4(3H)-one (120)

Triethyl orthoformate (1.69 ml, 10.2 mmol) and p-toluenesulfonic acid (117 mg, 0.679 mmol) were treated with (S)-3′-amino-6″-cyclopropyl-N-(3,3, 3-trifluoro-2-hydroxypropyl)-[3,2′:6′,3″-terpyridine]-4′-carboxamide (301 mg, 0.679 mmol) was added in dioxane (3.4 ml). After 1 hour DMF (0.5 ml) was added and the reaction mixture was heated to 40° C. and stirred for 48 hours. The reaction mixture was quenched with sodium bicarbonate (pH>11). Water was added and the mixture was extracted with ethyl acetate. The combined organic layers are dried over anhydrous magnesium sulfate, concentrated and purified by silica gel column chromatography to give the title compound (S)-6-(6-cyclopropylpyridin-3-yl)-8-(pyridine-3- yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)pyrido[3,4-d]pyrimidin-4(3H)-one was given as a white solid (120, 115 mg, 37% ). ¹ H NMR (DMSO-d ₆ , 400 MHz): δ 1.02 (4H, d, J = 8.2 Hz), 2.23-2.17 (1H, m), 4.08 (1H, dd, J = 14.1, 9.9 Hz), 4.45 (2H, d, J = 12.5 Hz), 6.78 (1H, d, J = 6.4 Hz), 7.47 (1H, d, J = 8.2Hz), 7.59 (1H, dd, J = 7.9, 4.8Hz), 8.49-8.47 (2H, m), 8.54 (2H, d, J = 11.8Hz) ), 8.70 (1H, d, J=4.8 Hz), 9.26 (1H, s), 9.32 (1H, s); MS (m/z): 454.2 [M+H] ⁺ ; >99% purity.

Table 12 lists compounds prepared by procedures analogous to those described for 120, substituting reactants 4, 5, and 6 for the groups indicated.

１０８は、１の合成の工程２（中間体Ｂ１の合成）に関して報告された手順に従って調製した。^１Ｈ ＮＭＲ（ＤＭＳＯ－ｄ_６，４００ＭＨｚ）：δ_Ｈ １．１７（３Ｈ，ｄ，Ｊ＝６．２Ｈｚ），３．７６（１Ｈ，ｄｄ，Ｊ＝１３．３，８．６Ｈｚ），３．９７（３Ｈ，ｓ），４．１６（１Ｈ，ｄｄ，Ｊ＝１３．３，３．２Ｈｚ），５．０８（１Ｈ，ｄ，Ｊ＝５．０Ｈｚ），８．０３（１Ｈ，ｄ，Ｊ＝８．３Ｈｚ），８．４６（１Ｈ，ｓ），８．４９（１Ｈ，ｓ），８．５３（１Ｈ，ｓ），８．８６（１Ｈ，ｓ），８．９３（１Ｈ，ｄ，Ｊ＝８．３Ｈｚ），９．６５（１Ｈ，ｓ）；ＭＳ（ｍ／ｚ）：４３１．１ ［Ｍ＋Ｈ］^＋；＞９９％純度． (R)-3-(2-hydroxypropyl)-8-(1-methyl-1H-pyrazol-4-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido [3,4 Preparation of d]pyrimidin-4(3H)-one (108)

108 was prepared following the procedure reported for step 2 of the synthesis of 1 (synthesis of intermediate B1). ¹ H NMR (DMSO-d ₆ , 400 MHz): δ _H 1.17 (3H, d, J=6.2 Hz), 3.76 (1H, dd, J=13.3, 8.6 Hz), 3. 97 (3H, s), 4.16 (1H, dd, J = 13.3, 3.2 Hz), 5.08 (1H, d, J = 5.0 Hz), 8.03 (1H, d, J = 8.3 Hz), 8.46 (1H, s), 8.49 (1H, s), 8.53 (1H, s), 8.86 (1H, s), 8.93 (1H, d, J=8.3 Hz), 9.65 (1 H, s); MS (m/z): 431.1 [M+H] ⁺ ; >99% purity.

Table 13 lists compounds prepared by a procedure similar to that described for 108, substituting reactants 4, 5, and 6 for the groups indicated.

上記手順を、１０８に関して報告された手順に従って実施すると、ｔｅｒｔ－ブチル（３Ｒ，４Ｒ）－３－（６－（４－クロロフェニル）－４－オキソ－８－（ピリジン－３－イル）ピリド［３，４－ｄ］ピリミジン－３（４Ｈ）－イル）－４－ヒドロキシピロリジン－１－カルボキシレート（前駆体５）及び６－（４－クロロフェニル）－３－（（３Ｒ，４Ｒ）－４－ヒドロキシピロリジン－３－イル）－８－（ピリジン－３－イル）ピリド［３，４－ｄ］ピリミジン－４（３Ｈ）－オン（１３４）の混合物を与えた。 K-0004422 6-(4-chlorophenyl)-3-((3R,4R)-4-hydroxypyrrolidin-3-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidine-4 Preparation of (3H)-one (134) Step 1. tert-butyl (3R,4R)-3-(6-(4-chlorophenyl)-4-oxo-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-3(4H)-yl) - Preparation of 4-hydroxypyrrolidine-1-carboxylate (precursor 5)

When the above procedure is carried out according to the procedure reported for 108, tert-butyl(3R,4R)-3-(6-(4-chlorophenyl)-4-oxo-8-(pyridin-3-yl)pyrido[3 ,4-d]pyrimidin-3(4H)-yl)-4-hydroxypyrrolidine-1-carboxylate (precursor 5) and 6-(4-chlorophenyl)-3-((3R,4R)-4-hydroxy A mixture of pyrrolidin-3-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-ones (134) was given.

前駆体５及び１３４の混合物（２１８ｍｇ、０．４３ｍｍｏｌ）を、３．０ｍＬの４Ｍ ＨＣｌのジオキサン溶液に溶解させ、室温で１時間撹拌した。ジエチルエーテル（２．０ｍｌ）を加え、固体を遠心分離し、デカンテーションし、エーテルによりトリチュレートし、乾燥させた。固体を逆相カラムクロマトグラフィーにより精製すると、標記化合物６－（４－クロロフェニル）－３－（（３Ｒ，４Ｒ）－４－ヒドロキシピロリジン－３－イル）－８－（ピリジン－３－イル）ピリド［３，４－ｄ］ピリミジン－４（３Ｈ）－オン（１３４、１２０ｍｇ、０．２９、収率６７％）を白色の固体として与えた。^１Ｈ ＮＭＲ（ＤＭＳＯ－ｄ_６，４００ＭＨｚ）：δ_Ｈ ２．７０（１Ｈ，ｄｄ，Ｊ＝１１．５，４．７Ｈｚ），３．００（１Ｈ，ｄｄ，Ｊ＝１１．８，５．３Ｈｚ），３．２３（１Ｈ，ｄｄ，Ｊ＝１１．６，６．１Ｈｚ），３．２７（１Ｈ，ｓ），３．３４－３．３１（１Ｈ，ｍ），４．４３－４．４１（１Ｈ，ｍ），４．８３－４．８０（１Ｈ，ｍ），５．３１（１Ｈ，ｄ，Ｊ＝４．６Ｈｚ），７．６０－７．５５（３Ｈ，ｍ），８．３１（２Ｈ，ｄ，Ｊ＝８．４Ｈｚ），８．５４－８．５１（３Ｈ，ｍ），８．６８（１Ｈ，ｄｄ，Ｊ＝４．８，１．７Ｈｚ），９．３２（１Ｈ，ｄ，Ｊ＝２．１Ｈｚ）．ＭＳ（ｍ／ｚ）：４２０．１ ［Ｍ＋Ｈ］^＋；９９％純度． Step 2. 6-(4-Chlorophenyl)-3-((3R,4R)-4-hydroxypyrrolidin-3-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidine-4 (3H)-On (134)

A mixture of precursors 5 and 134 (218 mg, 0.43 mmol) was dissolved in 3.0 mL of 4 M HCl in dioxane and stirred at room temperature for 1 hour. Diethyl ether (2.0 ml) was added and the solid was centrifuged, decanted, triturated with ether and dried. Purification of the solid by reverse-phase column chromatography gives the title compound 6-(4-chlorophenyl)-3-((3R,4R)-4-hydroxypyrrolidin-3-yl)-8-(pyridin-3-yl)pyride [3,4-d]pyrimidin-4(3H)-one (134, 120 mg, 0.29, 67% yield) was given as a white solid. ¹ H NMR (DMSO-d ₆ , 400 MHz): δ _H 2.70 (1H, dd, J=11.5, 4.7 Hz), 3.00 (1H, dd, J=11.8, 5.3 Hz ), 3.23 (1H, dd, J = 11.6, 6.1 Hz), 3.27 (1H, s), 3.34-3.31 (1H, m), 4.43-4.41 (1H, m), 4.83-4.80 (1H, m), 5.31 (1H, d, J = 4.6 Hz), 7.60-7.55 (3H, m), 8.31 (2H, d, J = 8.4Hz), 8.54-8.51 (3H, m), 8.68 (1H, dd, J = 4.8, 1.7Hz), 9.32 (1H, d, J=2.1 Hz). MS (m/z): 420.1 [M+H] ⁺ ; 99% purity.

オルトギ酸トリエチル（１．７４ｍｌ、１０．５ｍｍｏｌ）及び１２．１Ｎ ＨＣｌ（１１５μｌ、１．３９ｍｍｏｌ）を、（Ｒ）－５－アミノ－６’－シクロプロピル－６－（１－メチル－１Ｈ－ピラゾール－４－イル）－Ｎ－（３，３，３－トリフルオロ－２－ヒドロキシプロピル）－［２，３’－ビピリジン］－４－カルボキサミド（Ｆ１９、３１１ｍｇ、０．６９７ｍｍｏｌ）のジオキサン（３．５ｍｌ）溶液に加えた。１時間後、ＤＭＦ（０．５ｍｌ）を加え、反応混合物を２４時間室温で撹拌した。反応混合物を重炭酸ナトリウム（ｐＨ＞＞１１）によりクエンチした。水を加え、酢酸エチルで抽出した。合わせた有機層を無水硫酸マグネシウムで乾燥させ、濃縮し、シリカゲルカラムクロマトグラフィーにより精製すると、標記化合物（Ｒ）－６－（６－シクロプロピルピリジン－３－イル）－８－（１－メチル－１Ｈ－ピラゾール－４－イル）－３－（３，３，３－トリフルオロ－２－ヒドロキシプロピル）ピリド［３，４－ｄ］ピリミジン－４（３Ｈ）－オンを与えた（１３５、１５２ｍｇ、４８％）。^１Ｈ ＮＭＲ（ＤＭＳＯ－ｄ_６，４００ＭＨｚ）：δ １．０３－１．００（４Ｈ，ｍ），２．２３－２．１８（１Ｈ，ｍ），３．９８（３Ｈ，ｓ），４．１０－４．０３（１Ｈ，ｍ），４．４９－４．４０（２Ｈ，ｍ），６．７９（１Ｈ，ｔ，Ｊ＝６．１Ｈｚ），７．４６（１Ｈ，ｄｄ，Ｊ＝８．１，４．９Ｈｚ），８．３１－８．３０（１Ｈ，ｍ），８．５０－８．４７（３Ｈ，ｍ），８．８４－８．８２（１Ｈ，ｍ），９．２９－９．２８（１Ｈ，ｍ）；ＭＳ（ｍ／ｚ）：４５７．１ ［Ｍ＋Ｈ］^＋；＞９９％純度． (R)-6-(6-cyclopropylpyridin-3-yl)-8-(1-methyl-1H-pyrazol-4-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl ) Preparation of pyrido[3,4-d]pyrimidin-4(3H)-one (135):

Triethyl orthoformate (1.74 ml, 10.5 mmol) and 12.1 N HCl (115 μl, 1.39 mmol) were added to (R)-5-amino-6′-cyclopropyl-6-(1-methyl-1H-pyrazole -4-yl)-N-(3,3,3-trifluoro-2-hydroxypropyl)-[2,3′-bipyridine]-4-carboxamide (F19, 311 mg, 0.697 mmol) in dioxane (3. 5 ml) was added to the solution. After 1 hour DMF (0.5 ml) was added and the reaction mixture was stirred for 24 hours at room temperature. The reaction mixture was quenched with sodium bicarbonate (pH>>11). Water was added and extracted with ethyl acetate. The combined organic layers are dried over anhydrous magnesium sulfate, concentrated and purified by silica gel column chromatography to give the title compound (R)-6-(6-cyclopropylpyridin-3-yl)-8-(1-methyl- 1H-pyrazol-4-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)pyrido[3,4-d]pyrimidin-4(3H)-one (135, 152 mg, 48%). ¹ H NMR (DMSO-d ₆ , 400 MHz): δ 1.03-1.00 (4H, m), 2.23-2.18 (1H, m), 3.98 (3H, s), 4. 10-4.03 (1H, m), 4.49-4.40 (2H, m), 6.79 (1H, t, J = 6.1 Hz), 7.46 (1H, dd, J = 8 .1, 4.9Hz), 8.31-8.30 (1H, m), 8.50-8.47 (3H, m), 8.84-8.82 (1H, m), 9.29 −9.28 (1H, m); MS (m/z): 457.1 [M+H] ⁺ ; >99% purity.

Table 14 lists compounds prepared by procedures analogous to those described for 139, substituting reactants 4, 5, and 6 with the groups indicated.

Compounds encompassed within this disclosure can be prepared by the procedures outlined in Scheme III and described in the Examples below.

中間体Ｇ１を、１１４の合成の工程３に従って調製した。ＭＳ（ｍ／ｚ）：３３８．０［Ｍ＋Ｈ］^＋。 3-((3S,4R)-4-hydroxytetrahydrofuran-3-yl)-8-(1-methyl-1H-pyrazol-4-yl)-6-(5-(trifluoromethyl)pyridin-2-yl ) Step for the preparation of pyrido[3,4-d]pyrimidin-4(3H)-one (137) 1. 3-Amino-6-chloro-N-((3S,4R)-4-hydroxytetrahydrofuran-3-yl )-2-(1-methyl-1H-pyrazol-4-yl)isonicotinamide (Intermediate G1)

Intermediate G1 was prepared according to step 3 of the synthesis of 114. MS (m/z): 338.0 [M+H] ^<+ >.

Table 15 shows intermediates made according to the steps shown above.

中間体Ｈ１を、９８の合成の最終工程に従って合成した。^１Ｈ－ＮＭＲ（ＤＭＳＯ－ｄ_６，４００ＭＨｚ）：δ_Ｈ ３．６２－３．５５（１Ｈ，ｍ），３．９２（３Ｈ，ｓ），４．１１－４．０６（２Ｈ，ｍ），４．１６（１Ｈ，ｄｄ，Ｊ＝１０．０，５．６Ｈｚ），４．５２（１Ｈ，ｓ），４．９２（１Ｈ，ｓ），５．７１（１Ｈ，ｄ，Ｊ＝４．１Ｈｚ），７．７９－７．７６（１Ｈ，ｍ），８．３２（１Ｈ，ｓ），８．３３（１Ｈ，ｓ），８．７３（１Ｈ，ｓ）；ＭＳ（ｍ／ｚ）：３４８．０ ［Ｍ＋Ｈ］^＋；＞９０％純度． Step 2. 6-Chloro-3-((3S,4R)-4-hydroxytetrahydrofuran-3-yl)-8-(1-methyl-1H-pyrazol-4-yl)pyrido[3,4-d]pyrimidine Preparation of -4(3H)-one (Intermediate H1)

Intermediate H1 was synthesized following the final steps of the synthesis of 98. ¹ H-NMR (DMSO-d ₆ , 400 MHz): δ _H 3.62-3.55 (1H, m), 3.92 (3H, s), 4.11-4.06 (2H, m), 4.16 (1H, dd, J = 10.0, 5.6Hz), 4.52 (1H, s), 4.92 (1H, s), 5.71 (1H, d, J = 4.1Hz) ), 7.79-7.76 (1H, m), 8.32 (1H, s), 8.33 (1H, s), 8.73 (1H, s); MS (m/z): 348 .0 [M+H] ⁺ ; >90% purity.

The intermediates in Table 16 were synthesized according to the steps described above.

Table 17 shows intermediates synthesized according to the final steps of the synthesis of 108.

６－クロロ－３－（（３Ｓ，４Ｒ）－４－ヒドロキシテトラヒドロフラン－３－イル）－８－（１－メチル－１Ｈ－ピラゾール－４－イル）ピリド［３，４－ｄ］ピリミジン－４（３Ｈ）－オン（Ｈ１、２００ｍｇ、０．５７５ｍｍｏｌ）、クロロ（２－ジシクロヘキシルホスフィノ－２’，４’，６’－トリイソプロピル－１，１’－ビフェニル）［２－（２－アミノエチル）フェニル）］パラジウム（ＩＩ）［Ｘｐｈｏｓ Ｐｄ Ｇ１］、（２２．２４ｍｇ、０．０２９ｍｍｏｌ）、及び５－トリフルオロメチル－２－ピリジルボロン酸ＭＩＤＡエステル（２６０ｍｇ、０．８６３ｍｍｏｌ）を、空気の下で、撹拌子を備えた加熱乾燥させた１０ｍＬ圧力バイアルに加えた。バイアルをアルゴンで満たし、次いで１－メチル－２－ピロリドン（ＮＭＰ）（４ｍＬ）を加え、それに続いてジエタノールアミン（０．０５５ｍｌ、０．５７５ｍｍｏｌ）、Ｋ_３ＰＯ_４（６１０ｍｇ、２．８７ｍｍｏｌ）、及びＣｕ（ＯＡｃ）_２（５２．２ｍｇ、０．２８８ｍｍｏｌ）を加えて、バイアルをキャップで密封した。反応混合物を１００℃に加熱し、１８時間撹拌した。次いでバイアルを冷却した。反応混合物に８ｍＬの２Ｎ ＨＣｌを加え、生じた溶液を１０分間撹拌し、次いで１Ｎ ＮａＯＨ（１２ｍＬ）を加え、生じた溶液を２０分間撹拌した。形成した沈殿物を濾過し、回収し、乾燥させた。シリカゲルカラムクロマトグラフィーによる沈殿物の精製は標記化合物３－（（３Ｓ，４Ｒ）－４－ヒドロキシテトラヒドロフラン－３－イル）－８－（１－メチル－１Ｈ－ピラゾール－４－イル）－６－（５－（トリフルオロメチル）ピリジン－２－イル）ピリド［３，４－ｄ］ピリミジン－４（３Ｈ）－オンを与えた（１３７、１５１ｍｇ、収率５７％）。^１Ｈ－ＮＭＲ（ＤＭＳＯ－ｄ_６，４００ＭＨｚ）：δ_Ｈ ３．６４（１Ｈ，ｄ，Ｊ＝９．３Ｈｚ），３．９８（４Ｈ，ｓ），４．１５（３Ｈ，ｓ），４．２０（１Ｈ，ｄ，Ｊ＝８．１Ｈｚ），４．５７（２Ｈ，ｓ），５．０１（２Ｈ，ｓ），５．７５（２Ｈ，ｓ），８．３９（３Ｈ，ｄ，Ｊ＝１１．３Ｈｚ），８．５５（１Ｈ，ｓ），８．８７－８．８１（４Ｈ，ｍ），９．１４（１Ｈ，ｓ）；ＭＳ（ｍ／ｚ）：４５９．１ ［Ｍ＋Ｈ］^＋；＞９９％純度． Step 3. Method A: 3-((3S,4R)-4-hydroxytetrahydrofuran-3-yl)-8-(1-methyl-1H-pyrazol-4-yl)-6-(5-(trifluoromethyl)pyridine- Preparation of 2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (137):

6-chloro-3-((3S,4R)-4-hydroxytetrahydrofuran-3-yl)-8-(1-methyl-1H-pyrazol-4-yl)pyrido[3,4-d]pyrimidine-4 ( 3H)-one (H1, 200 mg, 0.575 mmol), chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2-aminoethyl) Phenyl)]palladium(II) [Xphos Pd G1], (22.24 mg, 0.029 mmol), and 5-trifluoromethyl-2-pyridyl boronic acid MIDA ester (260 mg, 0.863 mmol) were treated under air. was added to a heat dried 10 mL pressure vial equipped with a stir bar. The vial was filled with argon, then 1-methyl-2-pyrrolidone (NMP) (4 mL) was added, followed by diethanolamine (0.055 ml, 0.575 mmol), K ₃ PO ₄ (610 mg, 2.87 mmol), and Cu(OAc) ₂ (52.2 mg, 0.288 mmol) was added and the vial was sealed with a cap. The reaction mixture was heated to 100° C. and stirred for 18 hours. The vial was then cooled. 8 mL of 2N HCl was added to the reaction mixture and the resulting solution was stirred for 10 minutes, then 1N NaOH (12 mL) was added and the resulting solution was stirred for 20 minutes. The precipitate that formed was filtered, collected and dried. Purification of the precipitate by silica gel column chromatography gave the title compound 3-((3S,4R)-4-hydroxytetrahydrofuran-3-yl)-8-(1-methyl-1H-pyrazol-4-yl)-6-( 5-(Trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one was afforded (137, 151 mg, 57% yield). ¹ H-NMR (DMSO-d ₆ , 400 MHz): δ _H 3.64 (1H, d, J=9.3 Hz), 3.98 (4H, s), 4.15 (3H, s), 4. 20 (1H, d, J = 8.1Hz), 4.57 (2H, s), 5.01 (2H, s), 5.75 (2H, s), 8.39 (3H, d, J = 11.3 Hz), 8.55 (1 H, s), 8.87-8.81 (4 H, m), 9.14 (1 H, s); MS (m/z): 459.1 [M+H] ⁺ >99% purity.

Table 18 lists compounds prepared by a procedure similar to that described for 137, substituting reactants 6 and 7 for the groups indicated.

表１９は、１３７の合成の最終工程に使用した手順に従って合成した化合物を列記する。

Table 19 lists compounds synthesized according to the procedure used for the final step of the synthesis of 137.

Compounds encompassed within this disclosure can be prepared by the procedures outlined in Scheme V and described in the Examples below.

１５２は、１の合成の工程４に従って合成した。^１Ｈ ＮＭＲ（ＤＭＳＯ－ｄ_６，４００ＭＨｚ）：δ ３．６３（１Ｈ，ｄｄ，Ｊ＝９．６，３．３Ｈｚ），４．０７（１Ｈ，ｄｄ，Ｊ＝１０．０，４．０Ｈｚ），４．２２－４．１３（２Ｈ，ｍ），４．５８（１Ｈ，ｓ），５．００（１Ｈ，ｓ），５．７０（１Ｈ，ｄ，Ｊ＝４．４Ｈｚ），７．６０（３Ｈ，ｍ），８．３２（２Ｈ，ｄ，Ｊ＝８．４Ｈｚ），８．３７（１Ｈ，ｓ），８．５４（１Ｈ，ｓ），８．５６（１Ｈ，ｓ），８．７０（１Ｈ，ｓ），９．３４（１Ｈ，ｓ）；ＭＳ（ｍ／ｚ）：４２１．１ ［Ｍ＋Ｈ］^＋；＞９８％純度． 6-(4-chlorophenyl)-3-((3R,4S)-4-hydroxytetrahydrofuran-3-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidine-4(3H) - Preparation of On 18 (152):

152 was synthesized according to step 4 of the synthesis of 1. ¹ H NMR (DMSO-d ₆ , 400 MHz): δ 3.63 (1H, dd, J = 9.6, 3.3 Hz), 4.07 (1H, dd, J = 10.0, 4.0 Hz) , 4.22-4.13 (2H, m), 4.58 (1H, s), 5.00 (1H, s), 5.70 (1H, d, J = 4.4 Hz), 7.60 (3H, m), 8.32 (2H, d, J = 8.4 Hz), 8.37 (1 H, s), 8.54 (1 H, s), 8.56 (1 H, s), 8. 70 (1H, s), 9.34 (1H, s); MS (m/z): 421.1 [M+H] ⁺ ; >98% purity.

Table 20 lists compounds prepared by a procedure analogous to that described for 152, substituting reactants 6, 7, and 8 for the groups indicated.

メチル（Ｓ）－２－（４－オキソ－８－（ピリジン－３－イル）－６－（６－（トリフルオロメチル）ピリジン－３－イル）ピリド［３，４－ｄ］ピリミジン－３（４Ｈ）－イル）プロパノエート（１２７、７０ｍｇ、０．１５ｍｍｏｌ）を０．５ ＴＨＦに溶解させ、０．５ｍＬの１Ｍ ＬｉＯＨを滴加した。反応混合物を室温で撹拌したままにした。完了後、溶液をＡｍｂｅｒｌｉｔｅ－ＩＲ１２０［Ｈ］により酸性化し、濾過し、濃縮し、残渣を逆相クロマトグラフィーにより精製すると、標記化合物（Ｓ）－２－（４－オキソ－８－（ピリジン－３－イル）－６－（６－（トリフルオロメチル）ピリジン－３－イル）ピリド［３，４－ｄ］ピリミジン－３（４Ｈ）－イル）プロパン酸を与えた（１５５、３２ｍｇ、０．０７３ｍｍｏｌ、収率４７％）。^１Ｈ－ＮＭＲ（ＣＨ_３ＯＨ－ｄ_４，４００ＭＨｚ）：δ_Ｈ １．７６（３Ｈ，ｄ，Ｊ＝７．５Ｈｚ），５．４２（１Ｈ，ｄ，Ｊ＝７．５Ｈｚ），７．６２（１Ｈ，ｄｄ，Ｊ＝８．０，５．０Ｈｚ），７．９８（１Ｈ，ｄ，Ｊ＝８．３Ｈｚ），８．４６（１Ｈ，ｓ），８．６４（１Ｈ，ｄ，Ｊ＝４．８Ｈｚ），８．７７－８．７５（２Ｈ，ｍ），８．８６（１Ｈ，ｄ，Ｊ＝８．３Ｈｚ），９．４３（１Ｈ，ｓ），９．５６（１Ｈ，ｓ）． ＭＳ（ｍ／ｚ）：４４２．１ ［Ｍ＋Ｈ］．純度：９９％． (S)-2-(4-oxo-8-(pyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidine-3(4H )-yl)propanoic acid (155) preparation

methyl (S)-2-(4-oxo-8-(pyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidine-3 ( 4H)-yl)propanoate (127, 70 mg, 0.15 mmol) was dissolved in 0.5 THF and 0.5 mL of 1 M LiOH was added dropwise. The reaction mixture was left stirring at room temperature. After completion, the solution was acidified with Amberlite-IR120 [H], filtered, concentrated and the residue purified by reverse phase chromatography to give the title compound (S)-2-(4-oxo-8-(pyridine-3 -yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-3(4H)-yl)propanoic acid (155, 32 mg, 0.073 mmol , 47% yield). ¹ H-NMR (CH ₃ OH-d ₄ , 400 MHz): δ _H 1.76 (3H, d, J = 7.5 Hz), 5.42 (1H, d, J = 7.5 Hz), 7.62 (1H, dd, J = 8.0, 5.0 Hz), 7.98 (1H, d, J = 8.3 Hz), 8.46 (1H, s), 8.64 (1H, d, J = 4.8Hz), 8.77-8.75 (2H, m), 8.86 (1H, d, J = 8.3Hz), 9.43 (1H, s), 9.56 (1H, s) . MS (m/z): 442.1 [M+H]. Purity: 99%.

（Ｓ）－２－（４－オキソ－８－（ピリジン－３－イル）－６－（６－（トリフルオロメチル）ピリジン－３－イル）ピリド［３，４－ｄ］ピリミジン－３（４Ｈ）－イル）プロパン酸（１５５、１５０ｍｇ、０．３４ｍｍｏｌ）及びメチルアミン塩酸塩（３５ｍｇ、０．５１ｍｍｏｌ）を１．１ｍＬの無水ＮＭＰに溶解させた。Ｎ，Ｎ－ジイソプロピルエチルアミン（０．１８ｍＬ、１．０２ｍｍｏｌ）を加えた。溶液を氷水浴中で冷却し、ＨＡＴＵ（１５５ｍｇ、０．４０８ｍｍｏｌ）を加えた。反応混合物を放置して室温に温め、室温で撹拌したままにした。完了後、反応物を水でクエンチし、ＥｔＯＡｃにより希釈した。有機相を、飽和ＮａＨＣＯ_３、ブラインで洗浄し、無水硫酸ナトリウムで乾燥させ、濃縮した。残渣を順相クロマトグラフィーにより精製すると、標記化合物（Ｓ）－Ｎ－メチル－２－（４－オキソ－８－（ピリジン－３－イル）－６－（６－（トリフルオロメチル）ピリジン－３－イル）ピリド［３，４－ｄ］ピリミジン－３（４Ｈ）－イル）プロパンアミドを与えた（１５６、９４ｍｇ、０．２１ｍｍｏｌ、収率６１％）。^１Ｈ－ＮＭＲ（ＣＨ_３ＯＨ－ｄ_４，４００ＭＨｚ）：δ_Ｈ １．７８（３Ｈ，ｄ，Ｊ＝７．３Ｈｚ），２．７９（３Ｈ，ｓ），５．４８（１Ｈ，ｄ，Ｊ＝７．３Ｈｚ），７．６２（１Ｈ，ｄｄ，Ｊ＝７．９，５．０Ｈｚ），７．９７（１Ｈ，ｄ，Ｊ＝８．３Ｈｚ），８．５２（１Ｈ，ｓ），８．６５（１Ｈ，ｄ，Ｊ＝４．８Ｈｚ），８．７４－８．７３（２Ｈ，ｍ），８．８５（１Ｈ，ｄ，Ｊ＝８．４Ｈｚ），９．４３（１Ｈ，ｓ），９．５５（１Ｈ，ｓ）．ＭＳ（ｍ／ｚ）：４５５．１ ［Ｍ＋Ｈ］．純度：９９％． (S)-N-methyl-2-(4-oxo-8-(pyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidine Preparation of -3(4H)-yl)propanamide (156)

(S)-2-(4-oxo-8-(pyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidine-3(4H )-yl)propanoic acid (155, 150 mg, 0.34 mmol) and methylamine hydrochloride (35 mg, 0.51 mmol) were dissolved in 1.1 mL of anhydrous NMP. N,N-diisopropylethylamine (0.18 mL, 1.02 mmol) was added. The solution was cooled in an ice-water bath and HATU (155 mg, 0.408 mmol) was added. The reaction mixture was allowed to warm to room temperature and left stirring at room temperature. After completion, the reaction was quenched with water and diluted with EtOAc. The organic phase was washed with saturated NaHCO ₃ , brine, dried over anhydrous sodium sulfate and concentrated. Purification of the residue by normal phase chromatography gave the title compound (S)-N-methyl-2-(4-oxo-8-(pyridin-3-yl)-6-(6-(trifluoromethyl)pyridine-3). -yl)pyrido[3,4-d]pyrimidin-3(4H)-yl)propanamide (156, 94 mg, 0.21 mmol, 61% yield). ¹ H-NMR (CH OH _{- d} , 400 MHz): δ _H 1.78 (3H, d, J = 7.3 Hz), 2.79 (3H, s), 5.48 (1H, d, J = 7.3 Hz), 7.62 (1H, dd, J = 7.9, 5.0 Hz), 7.97 (1H, d, J = 8.3 Hz), 8.52 (1H, s), 8 .65 (1H, d, J = 4.8Hz), 8.74-8.73 (2H, m), 8.85 (1H, d, J = 8.4Hz), 9.43 (1H, s) , 9.55(1H,s). MS (m/z): 455.1 [M+H]. Purity: 99%.

１５７は、１５６に関して報告された手順に従って合成した。^１Ｈ－ＮＭＲ（ＤＭＳＯ－ｄ_６，４００ＭＨｚ）：δ_Ｈ １．６６（３Ｈ，ｄ，Ｊ＝７．３Ｈｚ），２．８７（３Ｈ，ｓ），３．１９（３Ｈ，ｓ），５．８８（１Ｈ，ｄ，Ｊ＝７．５Ｈｚ），７．５９（１Ｈ，ｄｄ，Ｊ＝７．９，４．７Ｈｚ），８．０６（１Ｈ，ｄ，Ｊ＝８．３Ｈｚ），８．５９－８．５７（１Ｈ，ｍ），８．６４（１Ｈ，ｓ），８．７０－８．６９（１Ｈ，ｍ），８．７４（１Ｈ，ｓ），８．９２（１Ｈ，ｄ，Ｊ＝８．４Ｈｚ），９．３７（１Ｈ，ｓ），９．６２（１Ｈ，ｓ）．ＭＳ（ｍ／ｚ）：４６９．１ ［Ｍ＋Ｈ］．純度：９９％． (S)-N,N-dimethyl-2-(4-oxo-8-(pyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido [3,4-d ] Preparation of pyrimidin-3(4H)-yl)propenamide (157)

157 was synthesized following the procedure reported for 156. ¹ H-NMR (DMSO-d ₆ , 400 MHz): δ _H 1.66 (3H, d, J=7.3 Hz), 2.87 (3H, s), 3.19 (3H, s), 5. 88 (1H, d, J = 7.5Hz), 7.59 (1H, dd, J = 7.9, 4.7Hz), 8.06 (1H, d, J = 8.3Hz), 8.59 -8.57 (1H, m), 8.64 (1H, s), 8.70-8.69 (1H, m), 8.74 (1H, s), 8.92 (1H, d, J = 8.4 Hz), 9.37 (1H, s), 9.62 (1H, s). MS (m/z): 469.1 [M+H]. Purity: 99%.

１５８は、１３８に関して報告された手順に従って合成した。^１Ｈ－ＮＭＲ（ＤＭＳＯ－ｄ６，４００ＭＨｚ）：δ １．６８（３Ｈ，ｄ，Ｊ＝７．３Ｈｚ），３．５３（２Ｈ，ｄｄ，Ｊ＝１７．９，９．２Ｈｚ），３．８３（１Ｈ，ｄｄ，Ｊ＝９．３，４．４Ｈｚ），３．９１（１Ｈ，ｔ，Ｊ＝７．３Ｈｚ），３．９９（１Ｈ，ｔ，Ｊ＝５．６Ｈｚ），４．０６（１Ｈ，ｓ），５．２９（１Ｈ，ｄ，Ｊ＝３．９Ｈｚ），５．４６－５．４０（１Ｈ，ｍ），７．６１（１Ｈ，ｄｄ，Ｊ＝７．９，４．９Ｈｚ），８．０７（１Ｈ，ｄ，Ｊ＝８．３Ｈｚ），８．５８（２Ｈ，ｔ，Ｊ＝７．８Ｈｚ），８．６４（１Ｈ，ｓ），８．７２（１Ｈ，ｄ，Ｊ＝４．８Ｈｚ），８．７６（１Ｈ，ｓ），８．９５（１Ｈ，ｄ，Ｊ＝８．４Ｈｚ），９．３８（１Ｈ，ｓ），９．６５（１Ｈ，ｓ）． ＭＳ（ｍ／ｚ）：５２７．１ ［Ｍ＋Ｈ］．純度：＞９９％ (S)-N-((3R,4S)-4-hydroxytetrahydrofuran-3-yl)-2-(4-oxo-8-(pyridin-3-yl)-6-(6-(trifluoromethyl) Preparation of pyridin-3-yl)pyrido[3,4-d]pyrimidin-3(4H)-yl)propenamide (158)

158 was synthesized following the procedure reported for 138. ¹ H-NMR (DMSO-d6, 400 MHz): δ 1.68 (3H, d, J = 7.3 Hz), 3.53 (2H, dd, J = 17.9, 9.2 Hz), 3.83 (1H, dd, J = 9.3, 4.4 Hz), 3.91 (1H, t, J = 7.3 Hz), 3.99 (1H, t, J = 5.6 Hz), 4.06 ( 1H, s), 5.29 (1H, d, J = 3.9Hz), 5.46-5.40 (1H, m), 7.61 (1H, dd, J = 7.9, 4.9Hz) ), 8.07 (1H, d, J = 8.3Hz), 8.58 (2H, t, J = 7.8Hz), 8.64 (1H, s), 8.72 (1H, d, J = 4.8 Hz), 8.76 (1 H, s), 8.95 (1 H, d, J = 8.4 Hz), 9.38 (1 H, s), 9.65 (1 H, s). MS (m/z): 527.1 [M+H]. Purity: >99%

６－クロロ－３－（２－ヒドロキシ－２－メチルプロピル）－８－（１Ｈ－ピラゾール－４－イル）ピリド［３，４－ｄ］ピリミジン－４（３Ｈ）－オン（Ｃ２３、１４０ｍｇ、０．４４ｍｍｏｌ）を無水ＴＨＦ（４．４ｍＬ）に懸濁させ、混合物を氷水浴により冷却した。ＮａＨ（油中６０％分散液、２６ｍｇ、１．１０ｍｍｏｌ）を加え、混合物を１０分間撹拌してから、ＳＥＭＣｌ（０．１９ｍＬ、１．１０ｍｍｏｌ）を加えた。完了後、反応を飽和ＮＨ_４Ｃｌ水溶液（２５ｍＬ）及び水（１０ｍＬ）によりクエンチした。水層を分離し、ＤＣＭで抽出した。合わせた有機層をブラインで洗浄し、無水硫酸ナトリウムで乾燥させ、濾過し、減圧下で濃縮した。残渣を順相クロマトグラフィーにより精製すると、標記化合物６－クロロ－３－（２－ヒドロキシ－２－メチルプロピル）－８－（１－（（２－（トリメチルシリル）エトキシ）メチル）－１Ｈ－ピラゾール－４－イル）ピリド［３，４－ｄ］ピリミジン－４（３Ｈ）－オンを与えた（６、１７０ｍｇ、０．３８ｍｍｏｌ、収率８６％）。^１Ｈ－ＮＭＲ（ＣＨＣｌ_３－ｄ，４００ＭＨｚ）：δ_Ｈ －０．０２（９Ｈ，ｓ），０．９４（２Ｈ，ｔ，Ｊ＝８．２Ｈｚ），１．２１（１Ｈ，ｄ，Ｊ＝６．１Ｈｚ），１．３３（６Ｈ，ｓ），３．６３（２Ｈ，ｔ，Ｊ＝８．３Ｈｚ），４．１０（２Ｈ，ｓ），５．５０（２Ｈ，ｓ），７．９２（１Ｈ，ｓ），８．２６（１Ｈ，ｓ），８．５４（１Ｈ，ｓ），８．７９（１Ｈ，ｓ）．ＭＳ（ｍ／ｚ）：４５０．２ ［Ｍ＋Ｈ］^＋． 3-(2-hydroxy-2-methylpropyl)-8-(1H-pyrazol-4-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidine Step for preparation of -4(3H)-one (159) 1. 6-Chloro-3-(2-hydroxy-2-methylpropyl)-8-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H - preparation of pyrazol-4-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (precursor 6)

6-chloro-3-(2-hydroxy-2-methylpropyl)-8-(1H-pyrazol-4-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (C23, 140 mg, 0 .44 mmol) was suspended in anhydrous THF (4.4 mL) and the mixture was cooled with an ice-water bath. NaH (60% dispersion in oil, 26 mg, 1.10 mmol) was added and the mixture was stirred for 10 minutes before adding SEMCl (0.19 mL, 1.10 mmol). After completion, the reaction was quenched with saturated aqueous NH ₄ Cl (25 mL) and water (10 mL). The aqueous layer was separated and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification of the residue by normal phase chromatography gave the title compound 6-chloro-3-(2-hydroxy-2-methylpropyl)-8-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole- 4-yl)pyrido[3,4-d]pyrimidin-4(3H)-one was given (6, 170 mg, 0.38 mmol, 86% yield). ¹ H-NMR (CHCl ₃ -d, 400 MHz): δ _H -0.02 (9H, s), 0.94 (2H, t, J = 8.2 Hz), 1.21 (1H, d, J = 6.1 Hz), 1.33 (6H, s), 3.63 (2H, t, J = 8.3 Hz), 4.10 (2H, s), 5.50 (2H, s), 7.92 (1 H, s), 8.26 (1 H, s), 8.54 (1 H, s), 8.79 (1 H, s). MS (m/z): 450.2 [M+H] ⁺ .

前駆体７を、上記で報告された手順に従って調製した。^１Ｈ－ＮＭＲ（ＣＨＣｌ_３－ｄ，４００ＭＨｚ）：δ_Ｈ －０．００１（９Ｈ，ｓ），０．９６（２Ｈ，ｔ，Ｊ＝８．３Ｈｚ），１．３５－１．３２（６Ｈ，ｍ），２．１２（１Ｈ，ｓ），３．６７（２Ｈ，ｔ，Ｊ＝８．３Ｈｚ），４．１５（２Ｈ，ｓ），５．５５（２Ｈ，ｓ），８．１０－８．０８（１Ｈ，ｍ），８．３２（１Ｈ，ｓ），８．６２（１Ｈ，ｓ），８．７０（１Ｈ，ｄ，Ｊ＝８．３Ｈｚ），８．８９（１Ｈ，ｓ），８．９７（１Ｈ，ｓ），９．０９（１Ｈ，ｓ）．ＭＳ（ｍ／ｚ）：５６１．２ ［Ｍ＋Ｈ］^＋． Step 2. 3-(2-Hydroxy-2-methylpropyl)-6-(5-(trifluoromethyl)pyridin-2-yl)-8-(1-((2-(trimethylsilyl)ethoxy)methyl)- Preparation of 1H-pyrazol-4-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (Precursor 7)

Precursor 7 was prepared according to the procedure reported above. ¹ H-NMR (CHCl ₃ -d, 400 MHz): δ _H -0.001 (9H, s), 0.96 (2H, t, J=8.3 Hz), 1.35-1.32 (6H, m), 2.12 (1H, s), 3.67 (2H, t, J = 8.3 Hz), 4.15 (2H, s), 5.55 (2H, s), 8.10-8 .08 (1H, m), 8.32 (1H, s), 8.62 (1H, s), 8.70 (1H, d, J = 8.3 Hz), 8.89 (1H, s), 8.97 (1H, s), 9.09 (1H, s). MS (m/z): 561.2 [M+H] ⁺ .

３－（２－ヒドロキシ－２－メチルプロピル）－６－（５－（トリフルオロメチル）ピリジン－２－イル）－８－（１－（（２－（トリメチルシリル）エトキシ）メチル）－１Ｈ－ピラゾール－４－イル）ピリド［３，４－ｄ］ピリミジン－４（３Ｈ）－オン（前駆体７、９０ｍｇ、０．１６ｍｍｏｌ）を１．６ｍＬの無水ＤＣＭに溶解させ、溶液を氷水浴により冷却した。トリフルオロ酢酸（０．６１ｍＬ、８．０ｍｍｏｌ）を加えた。反応混合物を０℃で３０分間撹拌したままにし、室温まで温めた。完了後、揮発物を減圧下で除去した。残渣をＥｔＯＡｃに吸収させ、飽和ＮａＨＣＯ_３、ブラインで洗浄し、無水硫酸ナトリウムで乾燥させ、濃縮した。残渣を順相クロマトグラフィーにより精製し、それに続いてＭｅＯＨ中で再結晶化すると、標記化合物３－（２－ヒドロキシ－２－メチルプロピル）－８－（１Ｈ－ピラゾール－４－イル）－６－（５－（トリフルオロメチル）ピリジン－２－イル）ピリド［３，４－ｄ］ピリミジン－４（３Ｈ）－オンを与えた（１５９、３５ｍｇ、収率５１％）。^１Ｈ－ＮＭＲ（ＣＨ_３ＯＨ－ｄ_４，４００ＭＨｚ）：δ_Ｈ １．２７（６Ｈ，ｓ），４．１３（２Ｈ，ｓ），８．２７－８．２５（１Ｈ，ｍ），８．４３（１Ｈ，ｓ），８．６７（１Ｈ，ｓ），８．８１－８．７９（１Ｈ，ｍ），８．９０（１Ｈ，ｓ），８．９９－８．９７（２Ｈ，ｍ）．ＭＳ（ｍ／ｚ）：４３１．１ ［Ｍ＋Ｈ］^＋．純度：９８％． Step 3. 3-(2-Hydroxy-2-methylpropyl)-8-(1H-pyrazol-4-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4- d] Preparation of pyrimidin-4(3H)-one (159)

3-(2-hydroxy-2-methylpropyl)-6-(5-(trifluoromethyl)pyridin-2-yl)-8-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole -4-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (precursor 7, 90 mg, 0.16 mmol) was dissolved in 1.6 mL of anhydrous DCM and the solution was cooled with an ice-water bath. . Trifluoroacetic acid (0.61 mL, 8.0 mmol) was added. The reaction mixture was left stirring at 0° C. for 30 minutes and allowed to warm to room temperature. After completion, volatiles were removed under reduced pressure. The residue was taken up in EtOAc, washed with saturated _NaHCO3 , brine, dried over anhydrous sodium sulfate and concentrated. Purification of the residue by normal phase chromatography followed by recrystallization in MeOH gives the title compound 3-(2-hydroxy-2-methylpropyl)-8-(1H-pyrazol-4-yl)-6- (5-(Trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one was afforded (159, 35 mg, 51% yield). ¹ H-NMR (CH ₃ OH-d ₄ , 400 MHz): δ _H 1.27 (6H, s), 4.13 (2H, s), 8.27-8.25 (1H, m), 8. 43 (1H, s), 8.67 (1H, s), 8.81-8.79 (1H, m), 8.90 (1H, s), 8.99-8.97 (2H, m) . MS (m/z): 431.1 [M+H] ⁺ . Purity: 98%.

オーブンで乾燥させたスクリューキャップ試験管に、ＣｕＩ（５３ｍｇ、０．２８ｍｍｏｌ）、４，７－ジメトキシ－１，１０－フェナントロリン（１３４ｍｇ、０．５６ｍｍｏｌ）、イミダゾール（９５ｍｇ、１．４ｍｍｏｌ）、６，８－ジクロロ－３－（２－ヒドロキシ－２－メチルプロピル）ピリド［３，４－ｄ］ピリミジン－４（３Ｈ）－オン（Ｂ２、４００ｍｇ、１．４ｍｍｏｌ）、ポリ（エチレングリコール）（２３３ｍｇ、０．０７ｍｍｏｌ）、Ｃｓ_２ＣＯ_３（９０８ｍｇ、２．８ｍｍｏｌ）、及び磁気撹拌子を入れた。次いで、無水ＮＭＰ（７ｍＬ）を加え、反応容器にゴム製セプタムを取り付けた。容器を、３サイクルにわたり、真空にしてアルゴンにより再び満たした。反応混合物を２～３時間１０８℃で加熱した。完了後、反応混合物を室温に冷却し、ジクロロメタンにより希釈し、ｃｅｌｉｔｅのプラグに通して濾過し、追加のジクロロメタンにより溶出させた。濾液を、飽和ＮａＨＣＯ_３、ブラインで洗浄し、無水硫酸ナトリウムで乾燥させ、濃縮し、生じた残渣を順相クロマトグラフィーにより精製すると、標記化合物６－クロロ－３－（２－ヒドロキシ－２－メチルプロピル）－８－（１Ｈ－イミダゾール－１－イル）ピリド［３，４－ｄ］ピリミジン－４（３Ｈ）－オンを与えた（前駆体８、２００ｍｇ、収率４５％）。^１Ｈ－ＮＭＲ（ＣＨ_３ＯＨ－ｄ_４，３００ＭＨｚ）：δ_Ｈ １．２４－１．２１（６Ｈ，ｍ），３．６５（１Ｈ，ｓ），４．１３（１Ｈ，ｓ），７．１８（１Ｈ，ｓ），８．０８（１Ｈ，ｓ），８．２６（１Ｈ，ｓ），８．４４（１Ｈ，ｓ），９．１１（１Ｈ，ｓ）．ＭＳ（ｍ／ｚ）：３１９．９ ［Ｍ＋Ｈ］^＋． 3-(2-hydroxy-2-methylpropyl)-8-(1H-imidazol-1-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidine Step for the preparation of -4(3H)-one (160) 1. 6-Chloro-3-(2-hydroxy-2-methylpropyl)-8-(1H-imidazol-1-yl)pyrido [3,4-d ] Preparation of pyrimidin-4(3H)-one (precursor 8)

CuI (53 mg, 0.28 mmol), 4,7-dimethoxy-1,10-phenanthroline (134 mg, 0.56 mmol), imidazole (95 mg, 1.4 mmol), 6, 8-dichloro-3-(2-hydroxy-2-methylpropyl)pyrido[3,4-d]pyrimidin-4(3H)-one (B2, 400 mg, 1.4 mmol), poly(ethylene glycol) (233 mg, 0.07 mmol), _{Cs2CO3 (} 908 mg, 2.8 mmol), and a magnetic stir bar. Anhydrous NMP (7 mL) was then added and the reaction vessel was fitted with a rubber septum. The vessel was evacuated and refilled with argon for three cycles. The reaction mixture was heated at 108° C. for 2-3 hours. After completion, the reaction mixture was cooled to room temperature, diluted with dichloromethane, filtered through a plug of celite and eluted with additional dichloromethane. The filtrate was washed with saturated NaHCO ₃ , brine, dried over anhydrous sodium sulfate and concentrated, and the resulting residue was purified by normal phase chromatography to give the title compound 6-chloro-3-(2-hydroxy-2-methyl). Propyl)-8-(1H-imidazol-1-yl)pyrido[3,4-d]pyrimidin-4(3H)-one was afforded (precursor 8, 200 mg, 45% yield). ¹ H-NMR (CH ₃ OH-d ₄ , 300 MHz): δ _H 1.24-1.21 (6H, m), 3.65 (1H, s), 4.13 (1H, s), 7. 18 (1 H, s), 8.08 (1 H, s), 8.26 (1 H, s), 8.44 (1 H, s), 9.11 (1 H, s). MS (m/z): 319.9 [M+H] ⁺ .

化合物１６０を、１２１に関して報告された手順に従って調製した。^１Ｈ－ＮＭＲ（ＣＨ_３ＯＨ－ｄ_４，４００ＭＨｚ）：δ_Ｈ １．２７（６Ｈ，ｓ），４．０８（２Ｈ，ｓ），７．１１（１Ｈ，ｓ），８．１４（１Ｈ，ｄ，Ｊ＝８．１Ｈｚ），８．２７（１Ｈ，ｓ），８．３７（１Ｈ，ｓ），８．４４（１Ｈ，ｄ，Ｊ＝８．３Ｈｚ），８．８７（２Ｈ，ｄ，Ｊ＝１６．９Ｈｚ），９．０６（１Ｈ，ｓ）．ＭＳ（ｍ／ｚ）：４３０．９ ［Ｍ＋Ｈ］．純度：９９％． Step 2. 3-(2-Hydroxy-2-methylpropyl)-8-(1H-imidazol-1-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4- d] Preparation of pyrimidin-4(3H)-one (160)

Compound 160 was prepared following the procedure reported for 121. ¹ H-NMR (CH ₃ OH-d ₄ , 400 MHz): δ _H 1.27 (6H, s), 4.08 (2H, s), 7.11 (1H, s), 8.14 (1H, d, J = 8.1 Hz), 8.27 (1 H, s), 8.37 (1 H, s), 8.44 (1 H, d, J = 8.3 Hz), 8.87 (2 H, d, J=16.9 Hz), 9.06 (1 H, s). MS (m/z): 430.9 [M+H]. Purity: 99%.

１６１を、１の合成の工程４に従って合成した。^１Ｈ－ＮＭＲ（ＣＨ_３ＯＨ－ｄ_４，３００ＭＨｚ）：δ_Ｈ １．３０（６Ｈ，ｓ），４．１６（２Ｈ，ｓ），７．２０（１Ｈ，ｓ），７．９８（１Ｈ，ｄ，Ｊ＝８．３Ｈｚ），８．４０（１Ｈ，ｓ），８．４８（１Ｈ，ｓ），８．６８（１Ｈ，ｓ），８．８２（１Ｈ，ｄ，Ｊ＝８．３Ｈｚ），９．１８（１Ｈ，ｓ），９．５１（１Ｈ，ｓ）．ＭＳ（ｍ／ｚ）：４３０．９ ［Ｍ＋Ｈ］．純度：９８％． 3-(2-hydroxy-2-methylpropyl)-8-(1H-imidazol-1-yl)-6-(6-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidine Preparation of -4(3H)-one (161)

161 was synthesized according to step 4 of the synthesis of 1. ¹ H-NMR (CH ₃ OH-d ₄ , 300 MHz): δ _H 1.30 (6H, s), 4.16 (2H, s), 7.20 (1H, s), 7.98 (1H, d, J = 8.3 Hz), 8.40 (1 H, s), 8.48 (1 H, s), 8.68 (1 H, s), 8.82 (1 H, d, J = 8.3 Hz) , 9.18(1H,s), 9.51(1H,s). MS (m/z): 430.9 [M+H]. Purity: 98%.

イミダゾール（９９ｍｇ、１．５ｍｍｏｌ）を、（Ｓ）－６，８－ジクロロ－３－（１－ヒドロキシプロパン－２－イル）ピリド［３，４－ｄ］ピリミジン－４（３Ｈ）－オン（Ｂ１、２００ｍｇ、０．７３ｍｍｏｌ）の無水ＤＭＦ溶液に加えた。溶液を氷水浴により冷却し、ＴＢＤＭＳＣｌ（１３２ｍｇ、０．８８ｍｍｏｌ）を加えた。反応混合物を静置して室温まで温め、２時間撹拌したままにした。完了後、反応をメタノールによりクエンチした。反応混合物をＥｔＯＡｃにより希釈し、飽和ＮａＨＣＯ_３及び水で連続的に洗浄した。有機相を無水硫酸ナトリウムで乾燥させ、濃縮すると、標記化合物（Ｓ）－３－（１－（（ｔｅｒｔ－ブチルジメチルシリル）オキシ）プロパン－２－イル）－６，８－ジクロロピリド［３，４－ｄ］ピリミジン－４（３Ｈ）－オンを与えた（前駆体９、２８０ｍｇ、収率９９％）。^１Ｈ－ＮＭＲ（ＤＭＳＯ－ｄ_６，４００ＭＨｚ）：δ_Ｈ －０．０７（６Ｈ，ｄ，Ｊ＝１０．７Ｈｚ），０．７３（９Ｈ，ｓ），１．４１（３Ｈ，ｄ，Ｊ＝７．０Ｈｚ），３．９３－３．８１（２Ｈ，ｍ），４．８７（１Ｈ，ｓ），８．０５（１Ｈ，ｓ），８．６１（１Ｈ，ｓ）．ＭＳ（ｍ／ｚ）：３８７．９ ［Ｍ＋Ｈ］^＋． (S)-3-(1-hydroxypropan-2-yl)-8-(1H-imidazol-1-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido [3,4 Step 1 for the preparation of d]pyrimidin-4(3H)-one (162). (S)-3-(1-((tert-butyldimethylsilyl)oxy)propan-2-yl)-6,8-dichloropyrido[3,4-d]pyrimidin-4(3H)-one (precursor 9 ) preparation

Imidazole (99 mg, 1.5 mmol) was added to (S)-6,8-dichloro-3-(1-hydroxypropan-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (B1 , 200 mg, 0.73 mmol) in anhydrous DMF. The solution was cooled with an ice-water bath and TBDMSCl (132 mg, 0.88 mmol) was added. The reaction mixture was allowed to warm to room temperature and left stirring for 2 hours. After completion, the reaction was quenched with methanol. The reaction mixture was diluted with EtOAc and washed successively with saturated NaHCO ₃ and water. The organic phase is dried over anhydrous sodium sulfate and concentrated to give the title compound (S)-3-(1-((tert-butyldimethylsilyl)oxy)propan-2-yl)-6,8-dichloropyrido[3,4 -d]pyrimidin-4(3H)-one (precursor 9, 280 mg, 99% yield). ¹ H-NMR (DMSO-d ₆ , 400 MHz): δ _H −0.07 (6H, d, J=10.7 Hz), 0.73 (9 H, s), 1.41 (3H, d, J= 7.0 Hz), 3.93-3.81 (2H, m), 4.87 (1 H, s), 8.05 (1 H, s), 8.61 (1 H, s). MS (m/z): 387.9 [M+H] ⁺ .

中間体Ｐ１を、１６０の合成の工程１に報告された手順に従って合成した。ＭＳ（ｍ／ｚ）：４２０．０［Ｍ＋Ｈ］。 Step 2. (S)-3-(1-((tert-butyldimethylsilyl)oxy)propan-2-yl)-6-chloro-8-(1H-imidazol-1-yl)pyrido[3,4-d]pyrimidine Preparation of -4(3H)-one (P1)

Intermediate P1 was synthesized according to the procedure reported in step 1 of the synthesis of 160. MS (m/z): 420.0 [M+H].

Table 21 shows intermediates synthesized according to the steps described above.

（Ｓ）－３－（１－（（ｔｅｒｔ－ブチルジメチルシリル）オキシ）プロパン－２－イル）－６－クロロ－８－（１Ｈ－イミダゾール－１－イル）ピリド［３，４－ｄ］ピリミジン－４（３Ｈ）－オン（中間体Ｐ１、４６０ｍｇ、１．１ｍｍｏｌ）を無水ＴＨＦ（１１ｍＬ）に溶解させ、氷水浴により冷却した。テトラブチルアンモニウムフルオリド（ＴＨＦ中１．０Ｍ、１．３ｍＬ、１．３ｍｍｏｌ）を滴加し、溶液を１０分間撹拌した。完了後、反応混合物を飽和ＮＨ_４Ｃｌによりクエンチし、ＥｔＯＡｃで抽出した。有機相を回収し、水、ブラインで洗浄し、無水硫酸ナトリウムで乾燥させ、濃縮した。残渣をＭｅＯＨに吸収させ、沈殿物を回収して乾燥させると、標記化合物を与え、それをさらに精製せずに次の工程に使用した、（Ｓ）－６－クロロ－３－（１－ヒドロキシプロパン－２－イル）－８－（１Ｈ－イミダゾール－１－イル）ピリド［３，４－ｄ］ピリミジン－４（３Ｈ）－オン（中間体Ｑ１、３４０ｍｇ、１．１ｍｍｏｌ、定量的収率）。^１Ｈ－ＮＭＲ（ＤＭＳＯ－ｄ_６，３００ＭＨｚ）：δ_Ｈ １．４５－１．３９（３Ｈ，ｍ），３．８４－３．６２（２Ｈ，ｍ），４．９３－４．７８（１Ｈ，ｍ），５．０６－５．１１（１Ｈ，ｍ），７．１７－７．１４（１Ｈ，ｍ），８．０３－８．００（１Ｈ，ｍ），８．１２－８．０９（１Ｈ，ｍ），８．６６－８．６２（１Ｈ，ｍ），８．８５－８．８３（１Ｈ，ｍ）．ＭＳ（ｍ／ｚ）：３０５．９ ［Ｍ＋Ｈ］^＋． Step 3. (S)-6-chloro-3-(1-hydroxypropan-2-yl)-8-(1H-imidazol-1-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (Q1 ) preparation

(S)-3-(1-((tert-butyldimethylsilyl)oxy)propan-2-yl)-6-chloro-8-(1H-imidazol-1-yl)pyrido[3,4-d]pyrimidine -4(3H)-one (Intermediate P1, 460 mg, 1.1 mmol) was dissolved in anhydrous THF (11 mL) and cooled with an ice-water bath. Tetrabutylammonium fluoride (1.0 M in THF, 1.3 mL, 1.3 mmol) was added dropwise and the solution was stirred for 10 minutes. After completion, the reaction mixture was quenched with saturated _NH4Cl and extracted with EtOAc. The organic phase was collected, washed with water, brine, dried over anhydrous sodium sulfate and concentrated. The residue was taken up in MeOH and the precipitate was collected and dried to give the title compound, which was used in the next step without further purification, (S)-6-chloro-3-(1-hydroxy Propan-2-yl)-8-(1H-imidazol-1-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (intermediate Q1, 340 mg, 1.1 mmol, quantitative yield) . ¹ H-NMR (DMSO-d ₆ , 300 MHz): δ _H 1.45-1.39 (3H, m), 3.84-3.62 (2H, m), 4.93-4.78 (1H , m), 5.06-5.11 (1H, m), 7.17-7.14 (1H, m), 8.03-8.00 (1H, m), 8.12-8.09 (1 H, m), 8.66-8.62 (1 H, m), 8.85-8.83 (1 H, m). MS (m/z): 305.9 [M+H] ⁺ .

Table 22 lists intermediates synthesized according to the steps described above.

１６２は、１３７に関して報告された手順に従って調製した。^１Ｈ－ＮＭＲ（ＣＨ_３ＯＨ－ｄ_４，４００ＭＨｚ）：δ_Ｈ １．５７（３Ｈ，ｄ，Ｊ＝７．１Ｈｚ），３．８７（１Ｈ，ｄｄ，Ｊ＝１１．９，４．３Ｈｚ），３．９７（１Ｈ，ｄｄ，Ｊ＝１１．９，６．９Ｈｚ），５．０１（１Ｈ，ｔｄ，Ｊ＝７．１，４．４Ｈｚ），７．１９（１Ｈ，ｓ），８．２８（１Ｈ，ｄｄ，Ｊ＝８．３，２．２Ｈｚ），８．４３（１Ｈ，ｓ），８．５７（１Ｈ，ｓ），８．７０（１Ｈ，ｄ，Ｊ＝８．４Ｈｚ），９．０３（１Ｈ，ｓ），９．１５（１Ｈ，ｓ），９．１９（１Ｈ，ｓ）．ＭＳ（ｍ／ｚ）：４１６．９ ［Ｍ＋Ｈ］．純度：９８％． Step 4. (S)-3-(1-hydroxypropan-2-yl)-8-(1H-imidazol-1-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido [3,4 Preparation of d]pyrimidin-4(3H)-one (162)

162 was prepared following the procedure reported for 137. ¹ H-NMR (CH ₃ OH-d ₄ , 400 MHz): δ _H 1.57 (3H, d, J = 7.1 Hz), 3.87 (1H, dd, J = 11.9, 4.3 Hz) , 3.97 (1 H, dd, J=11.9, 6.9 Hz), 5.01 (1 H, td, J=7.1, 4.4 Hz), 7.19 (1 H, s), 8. 28 (1H, dd, J = 8.3, 2.2Hz), 8.43 (1H, s), 8.57 (1H, s), 8.70 (1H, d, J = 8.4Hz), 9.03 (1 H, s), 9.15 (1 H, s), 9.19 (1 H, s). MS (m/z): 416.9 [M+H]. Purity: 98%.

（Ｓ）－６－クロロ－３－（１－ヒドロキシプロパン－２－イル）－８－（１Ｈ－イミダゾール－１－イル）ピリド［３，４－ｄ］ピリミジン－４（３Ｈ）－オン（中間体Ｑ１、８５ｍｇ、０．２８ｍｍｏｌ）及び２－トリフルオロメチル－ピリジン－５－ボロン酸（８０ｍｇ、０．４２ｍｍｏｌ）を２ｍＬのトルエン－ＥｔＯＨ（２：１）に溶解させ、炭酸ナトリウム（１１８ｍｇ、１．１ｍｍｏｌ）を加えた。懸濁液を脱気し、アルゴンにより再び満たした（３サイクル）。テトラキス（トリフェニルホスフィン）パラジウム（３２ｍｇ、０．０２８ｍｍｏｌ）を加え、懸濁液を脱気し、アルゴンにより再び満たした（３サイクル）。反応混合物を８５℃にアルゴン下で加熱し、一晩撹拌したままにした。完了後、反応混合物を冷却し、ＥｔＯＡｃ中で希釈し、水及びブラインで洗浄した。有機相を無水硫酸ナトリウムで乾燥させた。溶液を濃縮し、順相カラムクロマトグラフィーにより精製し、それに続いてＭｅＯＨ中で結晶化すると、標記化合物（Ｓ）－３－（１－ヒドロキシプロパン－２－イル）－８－（１Ｈ－イミダゾール－１－イル）－６－（６－（トリフルオロメチル）ピリジン－３－イル）ピリド［３，４－ｄ］ピリミジン－４（３Ｈ）－オンを与えた（１６３、５２ｍｇ、収率４５％）。Ｈ－ＮＭＲ（ＣＨ_３ＯＨ－ｄ_４，３００ＭＨｚ）：δ_Ｈ ０．０８（３Ｈ，ｄ，Ｊ＝７．１Ｈｚ），２．４７－２．３８（２Ｈ，ｍ），３．５３（１Ｈ，ｓ），５．６９（１Ｈ，ｓ），６．４８（１Ｈ，ｄ，Ｊ＝８．３Ｈｚ），６．９１（１Ｈ，ｓ），７．０８（１Ｈ，ｓ），７．２０（１Ｈ，ｓ），７．３４（１Ｈ，ｄ，Ｊ＝８．４Ｈｚ），７．７０（１Ｈ，ｓ），８．０３（１Ｈ，ｓ）．ＭＳ（ｍ／ｚ）：４１６．９ ［Ｍ＋Ｈ］，純度：９９％． (S)-3-(1-hydroxypropan-2-yl)-8-(1H-imidazol-1-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido [3,4 Preparation of d]pyrimidin-4(3H)-one (163)

(S)-6-chloro-3-(1-hydroxypropan-2-yl)-8-(1H-imidazol-1-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (intermediate Compound Q1, 85 mg, 0.28 mmol) and 2-trifluoromethyl-pyridine-5-boronic acid (80 mg, 0.42 mmol) were dissolved in 2 mL of toluene-EtOH (2:1) and sodium carbonate (118 mg, 1 .1 mmol) was added. The suspension was degassed and refilled with argon (3 cycles). Tetrakis(triphenylphosphine)palladium (32 mg, 0.028 mmol) was added and the suspension was degassed and refilled with argon (3 cycles). The reaction mixture was heated to 85° C. under argon and left stirring overnight. After completion, the reaction mixture was cooled, diluted in EtOAc and washed with water and brine. The organic phase was dried over anhydrous sodium sulfate. The solution is concentrated and purified by normal phase column chromatography, followed by crystallization in MeOH to give the title compound (S)-3-(1-hydroxypropan-2-yl)-8-(1H-imidazole- 1-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one gave (163, 52 mg, 45% yield). . H-NMR (CH ₃ OH-d ₄ , 300 MHz): δ _H 0.08 (3H, d, J=7.1 Hz), 2.47-2.38 (2H, m), 3.53 (1H, s), 5.69 (1H, s), 6.48 (1H, d, J = 8.3 Hz), 6.91 (1H, s), 7.08 (1H, s), 7.20 (1H , s), 7.34 (1 H, d, J=8.4 Hz), 7.70 (1 H, s), 8.03 (1 H, s). MS (m/z): 416.9 [M+H], Purity: 99%.

Table 23 lists the compounds synthesized following the synthetic procedure reported for 163, substituting reactants in step 2.

（Ｓ）－６－クロロ－３－（１－ヒドロキシプロパン－２－イル）－８－（１－メチル－１Ｈ－ピラゾール－４－イル）ピリド［３，４－ｄ］ピリミジン－４（３Ｈ）－オン（Ｃ１０、１００ｍｇ、０．３１３ｍｍｏｌ）及び５－（４，４，５，５－テトラメチル－１，３，２－ジオキサボロラン－２－イル）－２－（トリフルオロメチル）チアゾール（９６．０ｍｇ、０．３４４ｍｍｏｌ）をジオキサンに溶解させた。Ｐｄ（ＯＡｃ）_２（７．０２ｍｇ、０．０３１ｍｍｏｌ）、トリフェニルホスフィン（１６．４ｍｇ、０．０６３ｍｍｏｌ）及びＫ_３ＰＯ_４（２６６ｍｇ、１．２５ｍｍｏｌ）を溶液に加えた。懸濁液を脱気し、アルゴンにより再び満たした（３サイクル）。反応混合物を９０℃に加熱し、１６時間撹拌した。反応混合物を酢酸エチルで抽出し、水及びブラインで洗浄した。合わせた有機層を無水硫酸マグネシウムで乾燥させ、濃縮し、シリカゲルカラムクロマトグラフィーにより精製すると、（Ｓ）－３－（１－ヒドロキシプロパン－２－イル）－８－（１－メチル－１Ｈ－ピラゾール－４－イル）－６－（２－（トリフルオロメチル）チアゾール－５－イル）ピリド［３，４－ｄ］ピリミジン－４（３Ｈ）－オンを与えた（１６８、２８ｍｇ、収率２０％）。^１Ｈ ＮＭＲ（ＤＭＳＯ－ｄ_６，４００ＭＨｚ）：δ １．４５（３Ｈ，ｄ，Ｊ＝７．０Ｈｚ），３．７１－３．６６（１Ｈ，ｍ），３．８２－３．７７（１Ｈ，ｍ），３．９７（３Ｈ，ｓ），４．９２－４．８７（１Ｈ，ｍ），５．１０（１Ｈ，ｔ，Ｊ＝５．４Ｈｚ），８．４５（１Ｈ，ｓ），８．５１（１Ｈ，ｓ），８．５８（１Ｈ，ｓ），８．７７（１Ｈ，ｓ），９．０３（１Ｈ，ｓ）．ＭＳ（ｍ／ｚ）：４３７．１ ［Ｍ＋Ｈ］^＋；９８％純度． (S)-3-(1-hydroxypropan-2-yl)-8-(1-methyl-1H-pyrazol-4-yl)-6-(2-(trifluoromethyl)thiazol-5-yl)pyrido Preparation of [3,4-d]pyrimidin-4(3H)-one (168)

(S)-6-chloro-3-(1-hydroxypropan-2-yl)-8-(1-methyl-1H-pyrazol-4-yl)pyrido[3,4-d]pyrimidine-4(3H) -one (C10, 100 mg, 0.313 mmol) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trifluoromethyl)thiazole (96. 0 mg, 0.344 mmol) was dissolved in dioxane. Pd(OAc) ₂ (7.02 mg, 0.031 mmol), triphenylphosphine (16.4 mg, 0.063 mmol) and _{K3PO4 (} 266 mg, 1.25 mmol) were added to the solution. The suspension was degassed and refilled with argon (3 cycles). The reaction mixture was heated to 90° C. and stirred for 16 hours. The reaction mixture was extracted with ethyl acetate and washed with water and brine. The combined organic layers are dried over anhydrous magnesium sulfate, concentrated and purified by silica gel column chromatography to give (S)-3-(1-hydroxypropan-2-yl)-8-(1-methyl-1H-pyrazole -4-yl)-6-(2-(trifluoromethyl)thiazol-5-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (168, 28 mg, 20% yield). ). ¹ H NMR (DMSO-d ₆ , 400 MHz): δ 1.45 (3H, d, J = 7.0 Hz), 3.71-3.66 (1H, m), 3.82-3.77 (1H , m), 3.97 (3H, s), 4.92-4.87 (1H, m), 5.10 (1H, t, J = 5.4 Hz), 8.45 (1H, s), 8.51 (1 H, s), 8.58 (1 H, s), 8.77 (1 H, s), 9.03 (1 H, s). MS (m/z): 437.1 [M+H] ⁺ ; 98% purity.

Table 24 lists compounds synthesized according to Synthetic Scheme V carrying out the steps according to the procedure reported in 168.

Compounds encompassed within this disclosure can be prepared by the procedures outlined in Scheme V and described in the Examples below.

ジメチルホルムアミド（２．０ｍｌ）を、密封したチューブ内の（Ｓ）－６，８－ジクロロ－３－（１－ヒドロキシプロパン－２－イル）ピリド［３，４－ｄ］ピリミジン－４（３Ｈ）－オン（Ｂ１、０．２００ｇ、０．７３ｍｍｏｌ）及び炭酸カリウム（０．４０３ｇ、２．９２ｍｍｏｌ）に加えた。ジエチルアミン（０．０５８６ｇ、０．８０３ｍｍｏｌ）を加え、反応混合物を１２０℃で２時間撹拌した。反応混合物を室温に冷却し、水を加え、混合物を酢酸エチルにより分配した。有機層を分離し、無水硫酸ナトリウムで乾燥させ、濃縮した。シリカゲルカラムクロマトグラフィーによる残渣の精製は、標記化合物（Ｓ）－６－クロロ－８－（ジエチルアミノ）－３－（１－ヒドロキシプロパン－２－イル）ピリド［３，４－ｄ］ピリミジン－４（３Ｈ）－オンを与えた（中間体Ｓ１、０．０６２ｇ、収率２７％）。^１Ｈ－ＮＭＲ（ＤＭＳＯ－ｄ_６，４００ＭＨｚ）：δ_Ｈ １．２１（６Ｈ，ｔ，Ｊ＝６．９Ｈｚ），１．３７（３Ｈ，ｄ，Ｊ＝７．１Ｈｚ），３．６４－３．６０（１Ｈ，ｍ），３．８３－３．７５（５Ｈ，ｍ），４．８２－４．７６（１Ｈ，ｍ），５．０４（１Ｈ，ｔ，Ｊ＝５．５Ｈｚ），７．０３（１Ｈ，ｓ），８．３２（１Ｈ，ｓ）；ＭＳ（ｍ／ｚ）：３１１．１ ［Ｍ＋Ｈ］^＋． (S)-8-(diethylamino)-3-(1-hydroxypropan-2-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidine-4 Preparation of (3H)-one (174) Step 1. Preparation of (S)-6-chloro-8-(diethylamino)-3-(1-hydroxypropan-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (Intermediate S1)

Dimethylformamide (2.0 ml) was added to (S)-6,8-dichloro-3-(1-hydroxypropan-2-yl)pyrido[3,4-d]pyrimidine-4(3H) in a sealed tube. -one (B1, 0.200 g, 0.73 mmol) and potassium carbonate (0.403 g, 2.92 mmol). Diethylamine (0.0586 g, 0.803 mmol) was added and the reaction mixture was stirred at 120° C. for 2 hours. The reaction mixture was cooled to room temperature, water was added and the mixture was partitioned with ethyl acetate. The organic layer was separated, dried over anhydrous sodium sulfate and concentrated. Purification of the residue by silica gel column chromatography gave the title compound (S)-6-chloro-8-(diethylamino)-3-(1-hydroxypropan-2-yl)pyrido[3,4-d]pyrimidine-4 ( 3H)-one was obtained (intermediate S1, 0.062 g, 27% yield). ¹ H-NMR (DMSO-d ₆ , 400 MHz): δ _H 1.21 (6H, t, J=6.9 Hz), 1.37 (3H, d, J=7.1 Hz), 3.64-3 .60 (1H, m), 3.83-3.75 (5H, m), 4.82-4.76 (1H, m), 5.04 (1H, t, J=5.5Hz), 7 .03 (1 H, s), 8.32 (1 H, s); MS (m/z): 311.1 [M+H] ⁺ .

Table 25 lists intermediates synthesized according to the steps described above.

１７４を調製する上記工程を、最終工程１に報告された手順に従って実施した。 Step 2. (S)-8-(diethylamino)-3-(1-hydroxypropan-2-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidine-4 Preparation of (3H)-one (174)

The above steps to prepare 174 were carried out according to the procedure reported in final step 1.

Table 26 lists the compounds synthesized according to the synthetic procedure reported for 174, substituting the reactants in Step 1 and Step 2.

（Ｓ）－６，８－ジクロロ－３－（１－ヒドロキシプロパン－２－イル）ピリド［３，４－ｄ］ピリミジン－４（３Ｈ）－オン（中間体Ｂ１、２００ｍｇ、０．７３ｍｍｏｌ）をトルエンに溶解させ、脱気してから、ＰｄＣｌ_２（２．６２ｍｇ、０．０１５ｍｍｏｌ）、ＣｓＦ（０．２２２ｇ、１．４６ｍｍｏｌ）、ＣｕＩ（０．０５６ｇ、０．２９２ｍｍｏｌ）、トリ－ターシャリーブチルホスフィン（０．２９２μｌ、０．２９２ｍｍｏｌ、ＴＨＦ中１．０Ｍ）、及び２－（トリブチルスタンニル）ピリジン（０．３４８ｍｇ、０．８０３ｍｍｏｌ）を加えた。溶液を再び脱気し、５０℃で一晩撹拌した。反応混合物をＥｔＯＡｃにより希釈し、水、ブラインで洗浄し、次いで無水硫酸ナトリウムで乾燥させた。溶媒を真空下で除去し、残渣をシリカゲルカラムクロマトグラフィー（ＣＨ_２Ｃｌ_２／ＭｅＯＨ）により精製すると、（Ｓ）－６－クロロ－３－（１－ヒドロキシプロパン－２－イル）－８－（ピリジン－２－イル）ピリド［３，４－ｄ］ピリミジン－４（３Ｈ）－オンを与えた（前駆体１０、５５．６ｍｇ、収率２４％）。^１Ｈ－ＮＭＲ（ＣＨＣｌ_３－ｄ，４００ＭＨｚ）：δ_Ｈ １．３４（３Ｈ，ｍ）， ３．９２（２Ｈ，ｔ，Ｊ＝４．４Ｈｚ），５．０７－５．００（１Ｈ，ｍ），７．４１（１Ｈ，ｄｄ，Ｊ＝７．３，１．９Ｈｚ），７．８９－７．８２（１Ｈ，ｍ），８．０３－７．９８（１Ｈ，ｍ），８．１９－８．１９（１Ｈ，ｍ），８．３４（１Ｈ，ｔ，Ｊ＝１．６Ｈｚ）， ８．９０－８．８３（１Ｈ，ｍ）；ＭＳ（ｍ／ｚ）：３１６．９ ［Ｍ＋Ｈ］^＋． (S)-3-(1-hydroxypropan-2-yl)-8-(pyridin-2-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido [3,4-d ] Pyrimidin-4(3H)-one (180) preparation step 1. (S)-6-chloro-3-(1-hydroxypropan-2-yl)-8-(pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (precursor 10 ) preparation

(S)-6,8-dichloro-3-(1-hydroxypropan-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (Intermediate B1, 200 mg, 0.73 mmol) Dissolve in toluene, degas, then PdCl ₂ (2.62 mg, 0.015 mmol), CsF (0.222 g, 1.46 mmol), CuI (0.056 g, 0.292 mmol), tri-tert-butyl. Phosphine (0.292 μl, 0.292 mmol, 1.0 M in THF) and 2-(tributylstannyl)pyridine (0.348 mg, 0.803 mmol) were added. The solution was degassed again and stirred at 50° C. overnight. The reaction mixture was diluted with EtOAc, washed with water, brine, then dried over anhydrous sodium sulfate. The solvent is removed under vacuum and the residue is purified by silica gel column chromatography (CH ₂ Cl ₂ /MeOH) to give (S)-6-chloro-3-(1-hydroxypropan-2-yl)-8-( Pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one was afforded (precursor 10, 55.6 mg, 24% yield). ¹ H-NMR (CHCl ₃ -d, 400 MHz): δ _H 1.34 (3H, m), 3.92 (2H, t, J = 4.4 Hz), 5.07-5.00 (1H, m ), 7.41 (1H, dd, J = 7.3, 1.9 Hz), 7.89-7.82 (1H, m), 8.03-7.98 (1H, m), 8.19 −8.19 (1H, m), 8.34 (1H, t, J=1.6 Hz), 8.90-8.83 (1H, m); MS (m/z): 316.9 [M+H ] ⁺ .

１８０を調製する上記工程を、１の最終工程に報告された手順に従って実施した。^１Ｈ－ＮＭＲ（ＤＭＳＯ－ｄ_６，３００ＭＨｚ）：δ_Ｈ １．４４－１．４０（３Ｈ，ｍ），３．７９－３．６４（２Ｈ，ｍ），４．９１（１Ｈ，ｓ），５．０９－５．０４（１Ｈ，ｍ），７．５５－７．５０（１Ｈ，ｍ），７．９２－７．８９（１Ｈ，ｍ），７．９９－７．９５（１Ｈ，ｍ），８．０７－８．０２（１Ｈ，ｍ），８．５１（１Ｈ，ｔ，Ｊ＝０．９Ｈｚ），８．７７－８．７４（１Ｈ，ｍ），８．８１（１Ｈ，ｔ，Ｊ＝０．８Ｈｚ），８．８９－８．８５（１Ｈ，ｍ），９．６０－９．５８（１Ｈ，ｍ）；ＭＳ（ｍ／ｚ）：４２７．９ ［Ｍ＋Ｈ］^＋；９９％純度． Step 2. (S)-3-(1-hydroxypropan-2-yl)-8-(pyridin-2-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido [3,4-d ] Preparation of pyrimidin-4(3H)-one (180)

The above steps to prepare 180 were carried out according to the procedure reported in 1 final step. ¹ H-NMR (DMSO-d ₆ , 300 MHz): δ _H 1.44-1.40 (3H, m), 3.79-3.64 (2H, m), 4.91 (1H, s), 5.09-5.04 (1H, m), 7.55-7.50 (1H, m), 7.92-7.89 (1H, m), 7.99-7.95 (1H, m ), 8.07-8.02 (1H, m), 8.51 (1H, t, J = 0.9 Hz), 8.77-8.74 (1H, m), 8.81 (1H, t , J = 0.8 Hz), 8.89-8.85 (1H, m), 9.60-9.58 (1H, m); MS (m/z): 427.9 [M + H] ⁺ ; 99 %purity.

（Ｓ）－６－（シクロヘキサ－１－エン－１－イル）－３－（１－ヒドロキシプロパン－２－イル）－８－（ピリジン－３－イル）ピリド［３，４－ｄ］ピリミジン－４（３Ｈ）－オン（７７、７６．２ｍｇ、０．２１０ｍｍｏｌ）及びＰｔＯ_２（４．７７ｍｇ、０．０２１ｍｍｏｌ）をＥｔＯＨ（３ｍｌ）に溶解させた。懸濁液を脱気し、アルゴンにより再び満たし、水素ガスで置換した。反応混合物を、水素雰囲気下で、３日間室温で撹拌した。反応混合物をＣｅｌｉｔｅに通して濾過し、濾液を濃縮し、シリカゲルカラムクロマトグラフィーにより精製すると、（Ｓ）－６－シクロヘキシル－３－（１－ヒドロキシプロパン－２－イル）－８－（ピリジン－３－イル）ピリド［３，４－ｄ］ピリミジン－４（３Ｈ）－オンを与えた（１８１、４６．０ｍｇ、収率６０％）。^１Ｈ－ＮＭＲ（ＣＨＣｌ_３－ｄ，３００ＭＨｚ）：δ １．８１－１．２９（９Ｈ，ｍ），１．９３－１．８７（２Ｈ，ｍ），２．０６（２Ｈ，ｄ，Ｊ＝１２．５Ｈｚ），２．９５－２．８５（１Ｈ，ｍ），３．９８（２Ｈ，ｄ，Ｊ＝４．６Ｈｚ），５．０６－４．９７（１Ｈ，ｍ），７．３８（１Ｈ，ｄｄ，Ｊ＝７．８，４．７Ｈｚ），７．９１（１Ｈ，ｓ），８．２２（１Ｈ，ｓ），８．４１（１Ｈ，ｄ，Ｊ＝８．０Ｈｚ），８．６１（１Ｈ，ｓ），９．３４（１Ｈ，ｓ）；ＭＳ（ｍ／ｚ）：３６５．０ ［Ｍ＋Ｈ］^＋；９９％純度． (S)-6-Cyclohexyl-3-(1-hydroxypropan-2-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (181) Preparation

(S)-6-(cyclohex-1-en-1-yl)-3-(1-hydroxypropan-2-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidine- 4(3H)-one (77, 76.2 mg, 0.210 mmol) and PtO ₂ (4.77 mg, 0.021 mmol) were dissolved in EtOH (3 ml). The suspension was degassed, refilled with argon and replaced with hydrogen gas. The reaction mixture was stirred at room temperature for 3 days under a hydrogen atmosphere. The reaction mixture is filtered through Celite and the filtrate is concentrated and purified by silica gel column chromatography to give (S)-6-cyclohexyl-3-(1-hydroxypropan-2-yl)-8-(pyridin-3). -yl)pyrido[3,4-d]pyrimidin-4(3H)-one (181, 46.0 mg, 60% yield). ¹ H-NMR (CHCl ₃ -d, 300 MHz): δ 1.81-1.29 (9H, m), 1.93-1.87 (2H, m), 2.06 (2H, d, J = 12.5 Hz), 2.95-2.85 (1H, m), 3.98 (2H, d, J = 4.6 Hz), 5.06-4.97 (1H, m), 7.38 ( 1H, dd, J=7.8, 4.7 Hz), 7.91 (1 H, s), 8.22 (1 H, s), 8.41 (1 H, d, J=8.0 Hz), 8. 61 (1H, s), 9.34 (1H, s); MS (m/z): 365.0 [M+H] ⁺ ; 99% purity.

上記手順を、１８０の合成の工程１に関して報告された手順に従って実施すると、（Ｓ）－３－（１－ヒドロキシプロパン－２－イル）－６－（ピリジン－２－イル）－８－（ピリジン－３－イル）ピリド［３，４－ｄ］ピリミジン－４（３Ｈ）－オン（１８２）を与えた。^１Ｈ－ＮＭＲ（ＤＭＳＯ－ｄ_６，３００ＭＨｚ）：δ_Ｈ １．４３（３Ｈ，ｄ，Ｊ＝７．０Ｈｚ），３．８４－３．６４（２Ｈ，ｍ），４．９１（１Ｈ，ｍ），５．０７（１Ｈ，ｔ，Ｊ＝５．６Ｈｚ），７．５０（１Ｈ，ｄｄｄ，Ｊ＝７．４，４．８，１．２Ｈｚ），７．５９（１Ｈ，ｄｄ，Ｊ＝７．９，４．８Ｈｚ），８．００（１Ｈ，ｔｄ，Ｊ＝７．８，１．７Ｈｚ），８．６０－８．５４（３Ｈ，ｍ），８．６９（１Ｈ，ｄｄ，Ｊ＝４．８，１．７Ｈｚ），８．７７－８．７５（１Ｈ，ｍ），９．０２（１Ｈ，ｓ），９．３６（１Ｈ，ｓ）；ＭＳ（ｍ／ｚ）：３６０．０ ［Ｍ＋Ｈ］^＋；９９％純度． (S)-3-(1-hydroxypropan-2-yl)-6-(pyridin-2-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidine-4(3H) - Preparation of On (182)

When the above procedure is carried out according to the procedure reported for step 1 of the synthesis of 180, (S)-3-(1-hydroxypropan-2-yl)-6-(pyridin-2-yl)-8-(pyridine -3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (182). ¹ H-NMR (DMSO-d ₆ , 300 MHz): δ _H 1.43 (3H, d, J = 7.0 Hz), 3.84-3.64 (2H, m), 4.91 (1H, m ), 5.07 (1H, t, J = 5.6 Hz), 7.50 (1H, ddd, J = 7.4, 4.8, 1.2 Hz), 7.59 (1H, dd, J = 7.9, 4.8 Hz), 8.00 (1H, td, J = 7.8, 1.7 Hz), 8.60-8.54 (3H, m), 8.69 (1H, dd, J = 4.8, 1.7 Hz), 8.77-8.75 (1 H, m), 9.02 (1 H, s), 9.36 (1 H, s); MS (m/z): 360. 0 [M+H] ⁺ ; 99% purity.

Table 27 lists compounds synthesized according to the synthetic procedure reported for 180.

上記手順を、４７の合成に関して報告された手順に従って実施すると、（Ｓ）－３－（１－ヒドロキシプロパン－２－イル）－６－（１－メチル－１Ｈ－１，２，３－トリアゾール－５－イル）－８－（ピリジン－３－イル）ピリド［３，４－ｄ］ピリミジン－４（３Ｈ）－オンを与えた（１８４、４０ｍｇ、１８％）。^１Ｈ－ＮＭＲ（ＤＭＳＯ－ｄ_６，３００ＭＨｚ）：δ １．４４（３Ｈ，ｄ，Ｊ＝７．０Ｈｚ），３．８４－３．６６（２Ｈ，ｍ），４．４２（３Ｈ，ｓ），４．９０（１Ｈ，ｔｄ，Ｊ＝７．１，４．９Ｈｚ），５．０９－５．０６（１Ｈ，ｍ），７．５９（１Ｈ，ｄｄ，Ｊ＝８．０，４．８Ｈｚ），８．５４－８．５０（２Ｈ，ｍ），８．５６（１Ｈ，ｓ），８．６０（１Ｈ，ｓ），８．７０（１Ｈ，ｄｄ，Ｊ＝４．８，１．６Ｈｚ），９．３１（１Ｈ，ｄ，Ｊ＝２．１Ｈｚ）．ＭＳ（ｍ／ｚ）：３６４．０ ［Ｍ＋Ｈ］^＋；９８％純度． (S)-3-(1-hydroxypropan-2-yl)-6-(1-methyl-1H-1,2,3-triazol-5-yl)-8-(pyridin-3-yl)pyrido [ Preparation of 3,4-d]pyrimidin-4(3H)-one (184)

Performing the above procedure according to the reported procedure for the synthesis of 47 yields (S)-3-(1-hydroxypropan-2-yl)-6-(1-methyl-1H-1,2,3-triazole- 5-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one was afforded (184, 40 mg, 18%). ¹ H-NMR (DMSO-d ₆ , 300 MHz): δ 1.44 (3H, d, J=7.0 Hz), 3.84-3.66 (2H, m), 4.42 (3H, s) , 4.90 (1H, td, J = 7.1, 4.9Hz), 5.09-5.06 (1H, m), 7.59 (1H, dd, J = 8.0, 4.8Hz) ), 8.54-8.50 (2H, m), 8.56 (1H, s), 8.60 (1H, s), 8.70 (1H, dd, J = 4.8, 1.6Hz ), 9.31 (1H, d, J=2.1 Hz). MS (m/z): 364.0 [M+H] ⁺ ; 98% purity.

ラセミの６－（４－クロロフェニル）－８－（ピリジン－３－イル）－３－（３，３，３－トリフルオロ－２－ヒドロキシプロピル）ピリド［３，４－ｄ］ピリミジン－４（３Ｈ）－オン（ｒａｃ－１８５、２０ｍｇ、０．０４５ｍｍｏｌ）をＳＦＣにより精製すると、標記化合物を与えた。（Ｒ）－６－（４－クロロフェニル）－８－（ピリジン－３－イル）－３－（３，３，３－トリフルオロ－２－ヒドロキシプロピル）ピリド［３，４－ｄ］ピリミジン－４（３Ｈ）－オン（６．９ｍｇ、収率３５％）。^１Ｈ－ＮＭＲ（ＣＨ_３ＯＨ－ｄ_４，４００ＭＨｚ）：δ_Ｈ ３．９８（１Ｈ，ｄｄ，Ｊ＝１３．７，９．６Ｈｚ），４．４５－４．４１（１Ｈ，ｍ），４．６２（１Ｈ，ｄｄ，Ｊ＝１３．８，３．０Ｈｚ），７．５３（２Ｈ，ｄ，Ｊ＝８．４Ｈｚ），７．６０（１Ｈ，ｄｄ，Ｊ＝７．９，４．９Ｈｚ），８．２３（２Ｈ，ｄ，Ｊ＝８．４Ｈｚ），８．３３（１Ｈ，ｓ），８．５８（１Ｈ，ｓ），８．６４－８．６２（１Ｈ，ｍ），８．７０（１Ｈ，ｄ，Ｊ＝８．０Ｈｚ），９．３８（１Ｈ，ｔ，Ｊ＝２．６Ｈｚ）．ＭＳ（ｍ／ｚ）：４４６．９ ［Ｍ＋Ｈ］．純度：９９％．（Ｓ）－６－（４－クロロフェニル）－８－（ピリジン－３－イル）－３－（３，３，３－トリフルオロ－２－ヒドロキシプロピル）ピリド［３，４－ｄ］ピリミジン－４（３Ｈ）－オン（６．４ｍｇ、収率３２％）。^１Ｈ－ＮＭＲ（ＣＨ_３ＯＨ－ｄ_４，４００ＭＨｚ）：δ_Ｈ ３．９９（１Ｈ，ｄｄ，Ｊ＝１３．７，９．７Ｈｚ），４．４６－４．４１（１Ｈ，ｍ），４．６２（１Ｈ，ｄｄ，Ｊ＝１３．６，２．８Ｈｚ），７．５４（２Ｈ，ｄ，Ｊ＝８．４Ｈｚ），７．６１（１Ｈ，ｄｄ，Ｊ＝８．０，４．９Ｈｚ），８．２４（２Ｈ，ｄ，Ｊ＝８．４Ｈｚ），８．３３（１Ｈ，ｓ），８．６０（１Ｈ，ｓ），８．６４－８．６２（１Ｈ，ｍ），８．７２－８．７０（１Ｈ，ｍ），９．３９（１Ｈ，ｄ，Ｊ＝２．５Ｈｚ）．ＭＳ（ｍ／ｚ）：４４６．９ ［Ｍ＋Ｈ］．純度：９９％． (R)-6-(4-chlorophenyl)-8-(pyridin-3-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)pyrido[3,4-d]pyrimidine-4 (3H)-one (185 enantiomer 1) and (S)-6-(4-chlorophenyl)-8-(pyridin-3-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl) Preparation of pyrido[3,4-d]pyrimidin-4(3H)-one (185 enantiomer 2)

Racemic 6-(4-chlorophenyl)-8-(pyridin-3-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)pyrido[3,4-d]pyrimidine-4 (3H )-one (rac-185, 20 mg, 0.045 mmol) was purified by SFC to give the title compound. (R)-6-(4-chlorophenyl)-8-(pyridin-3-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)pyrido[3,4-d]pyrimidine-4 (3H)-one (6.9 mg, 35% yield). ¹ H-NMR (CH ₃ OH-d ₄ , 400 MHz): δ _H 3.98 (1H, dd, J=13.7, 9.6 Hz), 4.45-4.41 (1H, m), 4 .62 (1H, dd, J = 13.8, 3.0 Hz), 7.53 (2H, d, J = 8.4 Hz), 7.60 (1H, dd, J = 7.9, 4.9 Hz ), 8.23 (2H, d, J = 8.4 Hz), 8.33 (1H, s), 8.58 (1H, s), 8.64-8.62 (1H, m), 8. 70 (1 H, d, J = 8.0 Hz), 9.38 (1 H, t, J = 2.6 Hz). MS (m/z): 446.9 [M+H]. Purity: 99%. (S)-6-(4-chlorophenyl)-8-(pyridin-3-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)pyrido[3,4-d]pyrimidine-4 (3H)-one (6.4 mg, 32% yield). ¹ H-NMR (CH ₃ OH-d ₄ , 400 MHz): δ _H 3.99 (1H, dd, J = 13.7, 9.7 Hz), 4.46-4.41 (1H, m), 4 .62 (1H, dd, J = 13.6, 2.8 Hz), 7.54 (2H, d, J = 8.4 Hz), 7.61 (1H, dd, J = 8.0, 4.9 Hz) ), 8.24 (2H, d, J = 8.4 Hz), 8.33 (1H, s), 8.60 (1H, s), 8.64-8.62 (1H, m), 8. 72-8.70 (1 H, m), 9.39 (1 H, d, J=2.5 Hz). MS (m/z): 446.9 [M+H]. Purity: 99%.

（Ｓ）－６－クロロ－３－（１－ヒドロキシプロパン－２－イル）－８－（ピリジン－３－イル）ピリド［３，４－ｄ］ピリミジン－４（３Ｈ）－オン（１００ｍｇ、１当量）及び５－メチル－２－（トリブチルスタンニル）ピリジン（１４５ｍｇ、０．１３１ｍＬ、１．２当量）をトルエン（３ｍＬ）に溶解させた。懸濁液を脱気し、アルゴンにより再び満たした（３サイクル）。テトラキス（トリフェニルホスフィン）パラジウム（７３ｍｇ、０．２当量）を加え、懸濁液を脱気し、アルゴンにより再び満たした（３サイクル）。反応混合物をアルゴン下で１００℃に加熱し、ＬＣ－ＭＳによりモニタリングした。２４時間後に、反応物に、ＫＦ及び水／ＭｅＯＨを加え、一晩撹拌した。反応混合物をｃｅｌｉｔｅに通して濾過し、濾液を濃縮し、２５分かけて０～１０％ＭｅＯＨとするＤＣＭ／ＭｅＯＨを使用してＣｏｍｂｉ－Ｆｌａｓｈ（登録商標）により精製した。得られた生成物（１００ｍｇ、収率８４％）を逆相クロマトグラフィーによりさらに精製すると、（Ｓ）－３－（１－ヒドロキシプロパン－２－イル）－６－（５－メチルピリジン－２－イル）－８－（ピリジン－３－イル）ピリド［３，４－ｄ］ピリミジン－４（３Ｈ）－オン（１８６）を白色の固体として与えた。^１Ｈ ＮＭＲ（ＤＭＳＯ－ｄ_６，，４００ＭＨｚ）：δ_Ｈ １．４２（３Ｈ，ｄ，Ｊ＝７．０Ｈｚ），２．３８（３Ｈ，ｓ），３．６７－３．６４（１Ｈ，ｍ），３．７７（１Ｈ，ｔ，Ｊ＝７．５Ｈｚ），４．９０（１Ｈ，ｄ，Ｊ＝７．９Ｈｚ），５．０７（１Ｈ，ｔ，Ｊ＝５．６Ｈｚ），７．５８（１Ｈ，ｄｄ，Ｊ＝７．９，４．９Ｈｚ），７．８１（１Ｈ，ｄ，Ｊ＝８．１Ｈｚ），８．４４（１Ｈ，ｄ，Ｊ＝８．１Ｈｚ），８．５５（２Ｈ，ｔ，Ｊ＝３．９Ｈｚ），８．５９（１Ｈ，ｓ），８．６８（１Ｈ，ｄ，Ｊ＝４．７Ｈｚ），８．９７（１Ｈ，ｓ），９．３４（１Ｈ，ｓ）． ＭＳ（ｍ／ｚ）：３７４．１ ［Ｍ＋Ｈ］．純度：＞９９％． (S)-3-(1-hydroxypropan-2-yl)-6-(5-methylpyridin-2-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidine-4 Preparation of (3H)-one (186)

(S)-6-chloro-3-(1-hydroxypropan-2-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (100 mg, 1 equivalents) and 5-methyl-2-(tributylstannyl)pyridine (145 mg, 0.131 mL, 1.2 equivalents) were dissolved in toluene (3 mL). The suspension was degassed and refilled with argon (3 cycles). Tetrakis(triphenylphosphine)palladium (73 mg, 0.2 eq) was added and the suspension was degassed and refilled with argon (3 cycles). The reaction mixture was heated to 100° C. under argon and monitored by LC-MS. After 24 hours, the reaction was added KF and water/MeOH and stirred overnight. The reaction mixture was filtered through celite and the filtrate was concentrated and purified by Combi-Flash® using DCM/MeOH to 0-10% MeOH over 25 minutes. The resulting product (100 mg, 84% yield) was further purified by reverse phase chromatography to give (S)-3-(1-hydroxypropan-2-yl)-6-(5-methylpyridine-2- yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (186) was given as a white solid. ¹ H NMR (DMSO-d , 400 MHz): δ _H 1.42 (3H, d, J = 7.0 Hz), 2.38 (3H, s), _3.67-3.64 (1H, m ), 3.77 (1H, t, J = 7.5 Hz), 4.90 (1H, d, J = 7.9 Hz), 5.07 (1H, t, J = 5.6 Hz), 7.58 (1H, dd, J = 7.9, 4.9 Hz), 7.81 (1H, d, J = 8.1 Hz), 8.44 (1H, d, J = 8.1 Hz), 8.55 ( 2H, t, J = 3.9Hz), 8.59 (1H, s), 8.68 (1H, d, J = 4.7Hz), 8.97 (1H, s), 9.34 (1H, s). MS (m/z): 374.1 [M+H]. Purity: >99%.

Table 28 lists compounds synthesized according to the synthetic procedure reported for 186.

工程１．（Ｓ）－６－クロロ－８－（シクロヘキサ－１－エン－１－イル）－３－（１－ヒドロキシプロパン－２－イル）ピリド［３，４－ｄ］ピリミジン－４（３Ｈ）－オンの調製

（Ｓ）－６，８－ジクロロ－３－（１－ヒドロキシプロパン－２－イル）ピリド［３，４－ｄ］ピリミジン－４（３Ｈ）－オン（中間体Ｂ１ ２００ｍｇ、０．７３ｍｍｏｌ）及びシクロヘキサ－１－エン－１－イルボロン酸（１０１ｍｇ、０．８０ｍｍｏｌ）をトルエン－ＥｔＯＨ（３：１、７ｍＬ）に溶解させ、炭酸ナトリウム（３０９ｍｇ、２．９ｍｍｏｌ）を加えた。懸濁液を脱気し、アルゴンにより再び満たした（３サイクル）。テトラキス（トリフェニルホスフィン）パラジウム（８４ｍｇ、０．０７ｍｍｏｌ）を加え、懸濁液を脱気し、アルゴンにより再び満たした（３サイクル）。反応混合物をアルゴン下で７５℃に加熱し、ＬＣ－ＭＳによりモニタリングした。一晩の反応後、反応混合物を冷却し、ＥｔＯＡｃにより希釈し、ｃｅｌｉｔｅに通して濾過し、濾液を、水、ブラインで洗浄し、硫酸ナトリウムで乾燥させた。残渣をシリカカラムにより精製すると、標記化合物を与えた（１３０ｍｇ、収率５６％）。１Ｈ ＮＭＲ（ＤＭＳＯ－ｄ６，４００ＭＨｚ）：δＨ １．３７（３Ｈ，ｄ，Ｊ＝７．０Ｈｚ），１．６８（４Ｈ，ｄ，Ｊ＝３０．１Ｈｚ），２．２５（２Ｈ，ｓ），３．７６－３．６０（２Ｈ，ｍ），４．８０（１Ｈ，ｄ，Ｊ＝７．９Ｈｚ），５．０３（１Ｈ，ｔ，Ｊ＝５．５Ｈｚ），６．７４（１Ｈ，ｓ），７．８２（１Ｈ，ｄ，Ｊ＝４．１Ｈｚ），８．４６（１Ｈ，ｓ）．ＭＳ（ｍ／ｚ）：３２０．１［Ｍ＋Ｈ］＋． (S)-8-cyclohexyl-3-(1-hydroxypropan-2-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidine-4 (3H )-one (189) preparation

Step 1. (S)-6-chloro-8-(cyclohex-1-en-1-yl)-3-(1-hydroxypropan-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one preparation of

(S)-6,8-dichloro-3-(1-hydroxypropan-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (Intermediate B1 200 mg, 0.73 mmol) and cyclohexa -1-en-1-ylboronic acid (101 mg, 0.80 mmol) was dissolved in toluene-EtOH (3:1, 7 mL) and sodium carbonate (309 mg, 2.9 mmol) was added. The suspension was degassed and refilled with argon (3 cycles). Tetrakis(triphenylphosphine)palladium (84 mg, 0.07 mmol) was added and the suspension was degassed and refilled with argon (3 cycles). The reaction mixture was heated to 75° C. under argon and monitored by LC-MS. After overnight reaction, the reaction mixture was cooled, diluted with EtOAc, filtered through celite and the filtrate was washed with water, brine and dried over sodium sulfate. The residue was purified by silica column to give the title compound (130 mg, 56% yield). 1H NMR (DMSO-d6, 400 MHz): δH 1.37 (3H, d, J = 7.0 Hz), 1.68 (4H, d, J = 30.1 Hz), 2.25 (2H, s), 3.76-3.60 (2H, m), 4.80 (1H, d, J = 7.9Hz), 5.03 (1H, t, J = 5.5Hz), 6.74 (1H, s ), 7.82 (1 H, d, J=4.1 Hz), 8.46 (1 H, s). MS (m/z): 320.1 [M+H]+.

空気の下で、撹拌子を備えた加熱乾燥させた圧力バイアルに、（Ｓ）－６－クロロ－８－（シクロヘキサ－１－エン－１－イル）－３－（１－ヒドロキシプロパン－２－イル）ピリド［３，４－ｄ］ピリミジン－４（３Ｈ）－オン（１２０ｍｇ、０．３８ｍｍｏｌ）、リン酸カリウム（３９９ｍｇ、１．８８ｍｍｏｌ）、（２－ジシクロヘキシルホスフィノ－２’，４’，６’－トリイソプロピル－１，１’－ビフェニル）［２－（２－アミノエチル）フェニル）］パラジウム（ＩＩ）クロリド［Ｘｐｈｏｓ Ｐｄ Ｇ１］（２８ｍｇ、０．３８ｍｍｏｌ）、及び５－トリフルオロメチル－２－ピリジルボロン酸ＭＩＤＡエステル（１７０ｍｇ、０．５６ｍｍｏｌ）、ジエタノールアミン（７９ｍｇ、０．７５ｍｍｏｌ）を加えた。２ｍＬのＮＭＰを加え、バイアルを脱気してからＣｕ（ＯＡｃ）２（６８ｍｇ、０．３８ｍｍｏｌ）を加えた。バイアルを、撹拌しながら１５時間１０８℃に加熱した。次いで、反応混合物を冷却し、ＥｔＯＡｃにより希釈し、ｃｅｌｉｔｅパッドに通して濾過した。濾液を、飽和ＮａＨＣＯ_３、水で洗浄し、濃縮し、順相に加えて逆相のｃｏｍｂｉ－ｆｌａｓｈ（登録商標）により精製すると、標記化合物を与えた（１００ｍｇ、収率６２％）。^１Ｈ ＮＭＲ（ＣＨ_３ＯＨ－ｄ４，４００ＭＨｚ）：δＨ １．５６（３Ｈ，ｄ，Ｊ＝７．１Ｈｚ），１．７８（２Ｈ，ｄ，Ｊ＝７．１Ｈｚ），１．８６（２Ｈ，ｄ，Ｊ＝７．１Ｈｚ），２．３４（２Ｈ，ｓ），２．７２（２Ｈ，ｓ），３．８４（１Ｈ，ｄｄ，Ｊ＝１１．９，４．１Ｈｚ），３．９６（１Ｈ，ｄｄ，Ｊ＝１１．８，６．７Ｈｚ），４．９６（１Ｈ，ｄ，Ｊ＝７．８Ｈｚ），６．７３（１Ｈ，ｓ），８．１９（１Ｈ，ｄ，Ｊ＝８．４Ｈｚ），８．３８（１Ｈ，ｓ），８．６０（１Ｈ，ｄ，Ｊ＝８．４Ｈｚ），８．９２（１Ｈ，ｓ），８．９５（１Ｈ，ｓ）．ＭＳ（ｍ／ｚ）：４３１．２［Ｍ＋Ｈ］＋．９８％純度． Step 2. (S)-8-(cyclohex-1-en-1-yl)-3-(1-hydroxypropan-2-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido [3 ,4-d]pyrimidin-4(3H)-one (188)

Under air, (S)-6-chloro-8-(cyclohex-1-en-1-yl)-3-(1-hydroxypropane-2- yl)pyrido[3,4-d]pyrimidin-4(3H)-one (120 mg, 0.38 mmol), potassium phosphate (399 mg, 1.88 mmol), (2-dicyclohexylphosphino-2′,4′, 6′-triisopropyl-1,1′-biphenyl)[2-(2-aminoethyl)phenyl)]palladium(II) chloride [Xphos Pd G1] (28 mg, 0.38 mmol), and 5-trifluoromethyl- 2-pyridyl boronic acid MIDA ester (170 mg, 0.56 mmol), diethanolamine (79 mg, 0.75 mmol) were added. 2 mL of NMP was added and the vial was degassed before adding Cu(OAc)2 (68 mg, 0.38 mmol). The vial was heated to 108° C. for 15 hours with stirring. The reaction mixture was then cooled, diluted with EtOAc and filtered through a celite pad. The filtrate was washed with saturated NaHCO ₃ , water, concentrated and purified by normal phase plus reverse phase combi-flash® to give the title compound (100 mg, 62% yield). ¹ H NMR (CH ₃ OH-d4, 400 MHz): δH 1.56 (3H, d, J=7.1 Hz), 1.78 (2H, d, J=7.1 Hz), 1.86 (2H, d, J = 7.1 Hz), 2.34 (2H, s), 2.72 (2H, s), 3.84 (1H, dd, J = 11.9, 4.1 Hz), 3.96 ( 1H, dd, J = 11.8, 6.7 Hz), 4.96 (1 H, d, J = 7.8 Hz), 6.73 (1 H, s), 8.19 (1 H, d, J = 8 .4 Hz), 8.38 (1 H, s), 8.60 (1 H, d, J=8.4 Hz), 8.92 (1 H, s), 8.95 (1 H, s). MS (m/z): 431.2 [M+H]+. 98% pure.

（Ｓ）－８－（シクロヘキサ－１－エン－１－イル）－３－（１－ヒドロキシプロパン－２－イル）－６－（５－（トリフルオロメチル）ピリジン－２－イル）ピリド［３，４－ｄ］ピリミジン－４（３Ｈ）－オン（７６ｍｇ、０．１８ｍｍｏｌ）及びＰｔＯ２（４ｍｇ、０．０１８ｍｍｏｌ）を１７ｍＬのＥｔＯＨに溶解させた。懸濁液を、３サイクルの間、脱気し、（バルーン中の）Ｈ_２ガスにより再び満たした。反応混合物を（バルーン中の）Ｈ_２ガスの下で、室温で撹拌し、ＬＣ－ＭＳによりモニタリングした。反応を２４時間後に停止し、ｃｅｌｉｔｅに通して濾過した。濾液を濃縮し、順相及び逆相のｃｏｍｂｉ－ｆｌａｓｈ（登録商標）により精製すると、標記化合物：（Ｓ）－８－シクロヘキシル－３－（１－ヒドロキシプロパン－２－イル）－６－（５－（トリフルオロメチル）ピリジン－２－イル）ピリド［３，４－ｄ］ピリミジン－４（３Ｈ）－オン（１８９）（１８ｍｇ、収率２４％）。１Ｈ ＮＭＲ（ＤＭＳＯ－ｄ６，４００ＭＨｚ）：δＨ １．３４（１Ｈ，ｓ），１．４１（３Ｈ，ｄ，Ｊ＝７．０Ｈｚ），１．４７（２Ｈ，ｄ，Ｊ＝１３．５Ｈｚ），１．７６（３Ｈ，ｔ，Ｊ＝１２．２Ｈｚ），１．８９（４Ｈ，ｔ，Ｊ＝１４．９Ｈｚ），３．６６－３．６３（１Ｈ，ｍ），３．７６（１Ｈ，ｓ），３．８４（１Ｈ，ｓ），４．８８（１Ｈ，ｓ），５．０５（１Ｈ，ｄ，Ｊ＝５．８Ｈｚ），８．３９（１Ｈ，ｄ，Ｊ＝８．４Ｈｚ），８．５７（１Ｈ，ｓ），８．６６（１Ｈ，ｄ，Ｊ＝８．４Ｈｚ），８．８７（１Ｈ，ｓ），９．１１（１Ｈ，ｓ）．ＭＳ（ｍ／ｚ）：４３３．２［Ｍ＋Ｈ］＋；純度９６％；（Ｓ）－８－シクロヘキシル－３－（１－ヒドロキシプロパン－２－イル）－６－（５－（トリフルオロメチル）ピリジン－２－イル）－２，３－ジヒドロピリド［３，４－ｄ］ピリミジン－４（１Ｈ）－オン（２２ｍｇ、収率２９％）を与えた。１Ｈ ＮＭＲ（ＤＭＳＯ－ｄ６，４００ＭＨｚ）：δＨ １．１４（３Ｈ，ｄ，Ｊ＝６．９Ｈｚ），１．２７（１Ｈ，ｄ，Ｊ＝１５．６Ｈｚ），１．４４（２Ｈ，ｄ，Ｊ＝１４．２Ｈｚ），１．６１（２Ｈ，ｔ，Ｊ＝１２．４Ｈｚ），１．７３（１Ｈ，ｂｒ ｓ），１．８２（４Ｈ，ｂｒ ｓ），２．９０（１Ｈ，ｓ），３．４９（２Ｈ，ｄ，Ｊ＝６．８Ｈｚ），４．５４（１Ｈ，ｄ，Ｊ＝８．２Ｈｚ），４．６２（２Ｈ，ｓ），４．８５（１Ｈ，ｄ，Ｊ＝５．８Ｈｚ），７．１１（１Ｈ，ｓ），８．２４（１Ｈ，ｄ，Ｊ＝８．５Ｈｚ），８．４３（１Ｈ，ｄ，Ｊ＝８．５Ｈｚ），８．５２（１Ｈ，ｓ），８．９６（１Ｈ，ｓ）．ＭＳ（ｍ／ｚ）：４３５．２ ［Ｍ＋Ｈ］＋；９９％純度． Step 3. (S)-8-cyclohexyl-3-(1-hydroxypropan-2-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidine-4 (3H )-one (189) preparation

(S)-8-(cyclohex-1-en-1-yl)-3-(1-hydroxypropan-2-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido [3 ,4-d]pyrimidin-4(3H)-one (76 mg, 0.18 mmol) and PtO2 (4 mg, 0.018 mmol) were dissolved in 17 mL of EtOH. The suspension was degassed and refilled with H2 gas (in a balloon) for ₃ cycles. The reaction mixture was stirred under H ₂ gas (in a balloon) at room temperature and monitored by LC-MS. The reaction was stopped after 24 hours and filtered through celite. The filtrate was concentrated and purified by normal and reverse phase combi-flash® to give the title compound: (S)-8-cyclohexyl-3-(1-hydroxypropan-2-yl)-6-(5 -(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (189) (18 mg, 24% yield). 1H NMR (DMSO-d6, 400 MHz): δH 1.34 (1H, s), 1.41 (3H, d, J = 7.0 Hz), 1.47 (2H, d, J = 13.5 Hz), 1.76 (3H, t, J = 12.2Hz), 1.89 (4H, t, J = 14.9Hz), 3.66-3.63 (1H, m), 3.76 (1H, s ), 3.84 (1H, s), 4.88 (1H, s), 5.05 (1H, d, J = 5.8 Hz), 8.39 (1H, d, J = 8.4 Hz), 8.57 (1 H, s), 8.66 (1 H, d, J=8.4 Hz), 8.87 (1 H, s), 9.11 (1 H, s). MS (m/z): 433.2 [M+H]+; 96% purity; (S)-8-cyclohexyl-3-(1-hydroxypropan-2-yl)-6-(5-(trifluoromethyl) Pyridin-2-yl)-2,3-dihydropyrido[3,4-d]pyrimidin-4(1H)-one (22 mg, 29% yield) was obtained. 1H NMR (DMSO-d6, 400 MHz): δH 1.14 (3H, d, J = 6.9 Hz), 1.27 (1H, d, J = 15.6 Hz), 1.44 (2H, d, J = 14.2 Hz), 1.61 (2H, t, J = 12.4 Hz), 1.73 (1H, br s), 1.82 (4H, br s), 2.90 (1H, s), 3.49 (2H, d, J = 6.8Hz), 4.54 (1H, d, J = 8.2Hz), 4.62 (2H, s), 4.85 (1H, d, J = 5 .8 Hz), 7.11 (1 H, s), 8.24 (1 H, d, J = 8.5 Hz), 8.43 (1 H, d, J = 8.5 Hz), 8.52 (1 H, s ), 8.96 (1H, s). MS (m/z): 435.2 [M+H]+; 99% purity.

（Ｓ）－６－クロロ－３－（１－ヒドロキシプロパン－２－イル）－８－（ピリジン－３－イル）ピリド［３，４－ｄ］ピリミジン－４（３Ｈ）－オン（２００ｍｇ、１当量）、ジメチルアミン．ＨＣｌ（７７ｍｇ、１．５当量）、モリブデンヘキサカルボニル（１６６ｍｇ、１当量）及びＸＰｈｏｓ（６０ｍｇ、０．２当量）の混合物に、ジオキサン（６ｍＬ）を加えた。懸濁液を脱気し、窒素で再び満たした（３サイクル）。酢酸パラジウム（ＩＩ）（１５ｍｇ、０．１当量）及びＫ_３ＰＯ_４を加え、懸濁液を脱気し、再び窒素で満たした（３サイクル）。反応混合物を１００℃で加熱し、ＬＣ－ＭＳによりモニタリングした。一晩後、反応混合物をｃｅｌｉｔｅに通して濾過し、ＥｔＯＡｃ、ＭｅＯＨで洗浄し、濾液を濃縮した。粗生成物（１９０）を、最初に、２５分かけて０～１０％ＭｅＯＨとするＤＣＭ／ＭｅＯＨにより溶出させるシリカゲルカラムクロマトグラフィーにより、それに続いて水／アセトニトリルを使用して逆相により精製すると、所望の生成物を与えた（９０ｍｇ、４０％）。^１Ｈ ＮＭＲ（ＤＭＳＯ－ｄ_６，４００ＭＨｚ）：δ_Ｈ １．４０（３Ｈ，ｄ，Ｊ＝７．０Ｈｚ），３．０５（７Ｈ，ｓ），３．６６（１Ｈ，ｓ），３．７６（１Ｈ，ｓ），４．８８－４．８３（１Ｈ，ｍ），５．０５（１Ｈ，ｔ，Ｊ＝５．３Ｈｚ），７．５５（１Ｈ，ｔ，Ｊ＝６．３Ｈｚ），８．１６（１Ｈ，ｓ），８．４１（１Ｈ，ｄ，Ｊ＝８．０Ｈｚ），８．５８（１Ｈ，ｓ），８．６６（１Ｈ，ｄ，Ｊ＝４．８Ｈｚ），９．２１（１Ｈ，ｓ）．ＭＳ（ｍ／ｚ）：４８８．０ ［Ｍ＋Ｈ］^＋；＞９９％純度． (S)-3-(1-hydroxypropan-2-yl)-N,N-dimethyl-4-oxo-8-(pyridin-3-yl)-3,4-dihydropyrido[3,4-d]pyrimidine Preparation of -6-carboxamide (190)

(S)-6-chloro-3-(1-hydroxypropan-2-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (200 mg, 1 equivalent), dimethylamine. To a mixture of HCl (77 mg, 1.5 eq), molybdenum hexacarbonyl (166 mg, 1 eq) and XPhos (60 mg, 0.2 eq) was added dioxane (6 mL). The suspension was degassed and refilled with nitrogen (3 cycles). Palladium(II) acetate (15 mg, 0.1 eq) and _{K3PO4 were} added and the suspension was degassed and refilled with nitrogen (3 cycles). The reaction mixture was heated at 100° C. and monitored by LC-MS. After overnight, the reaction mixture was filtered through celite, washed with EtOAc, MeOH and the filtrate was concentrated. The crude product (190) is first purified by silica gel column chromatography eluting with DCM/MeOH from 0-10% MeOH over 25 min followed by reverse phase using water/acetonitrile to It gave the desired product (90 mg, 40%). ¹ H NMR (DMSO-d ₆ , 400 MHz): δ _H 1.40 (3H, d, J=7.0 Hz), 3.05 (7H, s), 3.66 (1H, s), 3.76 (1H, s), 4.88-4.83 (1H, m), 5.05 (1H, t, J = 5.3 Hz), 7.55 (1H, t, J = 6.3 Hz), 8 .16 (1 H, s), 8.41 (1 H, d, J = 8.0 Hz), 8.58 (1 H, s), 8.66 (1 H, d, J = 4.8 Hz), 9.21 (1H, s). MS (m/z): 488.0 [M+H] ⁺ ; >99% purity.

(S)-3-(1-hydroxypropan-2-yl)-8-(1H-pyrazol-4-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido [3,4 Preparation of d]pyrimidin-4(3H)-one (191):
Compound 191 was prepared following the same procedure as in General Scheme IV above and the following protection strategy.

Table 29 lists intermediates synthesized according to general Scheme VI.

Table 30 lists compounds synthesized according to Synthetic Scheme VI above.

オーブンで乾燥させたマイクロ波バイアルに、ビス（ジ－ｔｅｒｔ－ブチル（４－ジメチルアミノフェニル）ホスフィン）ジクロロパラジウム（ＩＩ）（５．６ｍｇ、０．０５ｍｍｏｌ）、トリフルオロ（２－メトキシエチル）－λ４－ボラン、カリウム塩（４０ｍｇ、０．２４ｍｍｏｌ）、Ｃｓ２ＣＯ３（１５４ｍｇ、０．４７ｍｍｏｌ）及び（Ｓ）－６－クロロ－３－（１－ヒドロキシプロパン－２－イル）－８－（ピリジン－３－イル）ピリド［３，４－ｄ］ピリミジン－４（３Ｈ）－オン（５０ｍｇ、０．１６ｍｍｏｌ）を導入した。バイアルを密封し、脱気し、再びＮ^２で満たした。脱気したジオキサン－Ｈ２Ｏ（４：１、１ｍＬ）をシリンジにより加えた。次いで、反応混合物を１００℃に予備加熱した油浴内に配置し、２４時間この温度で撹拌した。完了後、反応混合物を室温に冷却し、ＥｔＯＡｃにより希釈し、ｃｅｌｉｔｅパッドに通して濾過した。濾液を、水、ブラインで洗浄し、硫酸ナトリウムで乾燥させ、濃縮し、順相クロマトグラフィーにより精製すると、標記化合物（１９２）を与えた。^１Ｈ ＮＭＲ（ＤＭＳＯ－ｄ６，４００ＭＨｚ）：δＨ １．３９（３Ｈ，ｄ，Ｊ＝７．０Ｈｚ），３．１７（２Ｈ，ｔ，Ｊ＝６．４Ｈｚ），３．２４（３Ｈ，ｓ），３．６４－３．６１（１Ｈ，ｍ），３．７７（３Ｈ，ｔ，Ｊ＝６．７Ｈｚ），４．８５（１Ｈ，ｓ），５．０３（１Ｈ，ｔ，Ｊ＝５．５Ｈｚ），７．５３（１Ｈ，ｔ，Ｊ＝６．２Ｈｚ），７．９３（１Ｈ，ｓ），８．４０（１Ｈ，ｄ，Ｊ＝７．９Ｈｚ），８．４７（１Ｈ，ｓ），８．６４（１Ｈ，ｄ，Ｊ＝４．６Ｈｚ），９．２０（１Ｈ，ｓ）．ＭＳ（ｍ／ｚ）：３４１．１ ［Ｍ＋Ｈ］＋；９６％純度． (S)-3-(1-hydroxypropan-2-yl)-6-(2-methoxyethyl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidine-4(3H)- Preparation of On (192)

Bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (5.6 mg, 0.05 mmol), trifluoro(2-methoxyethyl)- λ4-borane, potassium salt (40 mg, 0.24 mmol), Cs2CO3 (154 mg, 0.47 mmol) and (S)-6-chloro-3-(1-hydroxypropan-2-yl)-8-(pyridine-3 -yl)pyrido[3,4-d]pyrimidin-4(3H)-one (50 mg, 0.16 mmol) was introduced. The vial was sealed, evacuated and backfilled with ^N2 . Degassed dioxane-H2O (4:1, 1 mL) was added via syringe. The reaction mixture was then placed in an oil bath preheated to 100° C. and stirred at this temperature for 24 hours. After completion, the reaction mixture was cooled to room temperature, diluted with EtOAc and filtered through a celite pad. The filtrate was washed with water, brine, dried over sodium sulfate, concentrated and purified by normal phase chromatography to give the title compound (192). ¹ H NMR (DMSO-d6, 400 MHz): δH 1.39 (3H, d, J = 7.0 Hz), 3.17 (2H, t, J = 6.4 Hz), 3.24 (3H, s) , 3.64-3.61 (1H, m), 3.77 (3H, t, J=6.7 Hz), 4.85 (1H, s), 5.03 (1H, t, J=5. 5Hz), 7.53 (1H, t, J = 6.2Hz), 7.93 (1H, s), 8.40 (1H, d, J = 7.9Hz), 8.47 (1H, s) , 8.64 (1 H, d, J=4.6 Hz), 9.20 (1 H, s). MS (m/z): 341.1 [M+H]+; 96% purity.

(S)-3-(1-hydroxypropan-2-yl)-8-(2-methoxyethyl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d] Preparation of Pyrimidin-4(3H)-Ones (193) Compound 193 was prepared following the same procedure as in General Scheme IV above, following an alkyl-aryl coupling step following that of compound 192.

Table 31 lists intermediates synthesized according to general Scheme VII.

Table 32 lists compounds synthesized according to Synthetic Scheme VII above.

Example 2: DRE-Luciferase Reporter Assay AHR binds to the dioxin response element (DRE) upstream of the genes it activates. One measure of AHR activity is activation of a reporter gene, such as luciferase, downstream of one or more DRE elements. Luciferase activity would reflect activation and inhibition of AHR in cells expressing the his reporter. 20,000 human HepG2 liver cancer-AhR-Lucia reporter cells or human HT29 colon adenocarcinoma-AhR reporter cells or other cell lines stably transfected with DRE-luciferase reporter were plated (96-well, 384-well, or other Seed Eagle's Minimal Essential Medium, 10% heat-inactivated FBS, 1X non-essential amino acids, Pen-Strep (10,000 U/mL) and Normocin (100 ug/mL) in a plate) and placed in a CO ₂ incubator. Incubate overnight at 37° C. and treat with or without log dilutions of AhR antagonist starting at 100 uM.

One hour after seeding the cells, TCDD, kynurenine, ITE (2-(1H-indol-3-ylcarbonyl)-4-thiazolecarboxylic acid methyl ester), VAF347, BNF (β-naphthoflavone), FICZ (6- AHR activating ligands such as formylindolo(3,2-b)carbazole) or other AHR ligands at their specific _EC50 concentrations were added to cells with or without AHR antagonists.

Cells were incubated for 24 or 48 hours or another time point, then supernatants were analyzed for measurement of luciferase activity as a readout for AHR activation or inhibition. Luciferase was measured by Invivogen's commercial kit QUANTI-Luc™ assay solution kit according to the manufacturer's instructions.

Levels of luciferase with only agonist ligand added gave the highest signal and luciferase without antagonist had the lowest signal. _IC50 values were determined as the concentration that inhibited half the luciferase activity. The luciferase _IC50 levels of compounds of the present disclosure are reported in Table 33. "A" indicates IC ₅₀ values less than 100 nM, "B" indicates IC ₅₀ between 100 and 500 nM, "C" indicates IC ₅₀ greater than 500 nM, "D" indicates IC ₅₀ values generated from data. Show that you couldn't.

Example 3: CYP1A1 Gene Expression Assay Human and mouse colon cancer (CRC) cell lines, HT29 and HT26, respectively, American Type Culture Collection (ATCC), were plated 8 per well in sterile tissue culture treated 96-well plates (ThermoFisher). Seed at 0×10 ⁵ cells and grow overnight in DMEM complete medium (Gibco) at 37° C., 5% CO ₂ to achieve confluence. After incubation, the medium is aspirated from the cell monolayer and the tissue is then washed with 200 μL of warmed PBS solution before adding 190 μL of pre-warmed growth medium to each well. The AhR antagonist of interest is diluted at 20-fold concentration in growth medium containing 2% DMSO and 10 μL of compound solution is added to each well in triplicate. After 1 hour, TCDD, kynurenine, ITE (2-(1H-indol-3-ylcarbonyl)-4-thiazolecarboxylic acid methyl ester), VAF347, BNF (β-naphthoflavone), FICZ (6-formylindolo ( 3,2-b) AHR activating ligands such as carbazole or other AHR ligands are added with or without AHR antagonists for 24 hours, after which the medium is removed and stored at -80 degrees for later cytokine analysis. At the end of the incubation, the media is aspirated from the CRC cells and the cells are washed with 100 μL of cold PBS solution RNA is purified by TaqMan™ Gene Expression Cells-to-CT™ according to the manufacturer's protocol. Kit (ThermoFisher) QuantStudio 6 Flex (Applied Biosciences) is used to analyze CYP1A1 mRNA levels using GAPDH as an endogenous control TaqMan™ probe sets for both genes from ThermoFisher Samples were run in triplicate and data were analyzed using QuantStudio software and reported as linear and log2(ΔΔCT) values Statistical analysis was performed for CYP1A1 in the presence of each individual compound relative to the vehicle negative control. A two-tailed t-test comparing levels is performed.Compounds with _IC50s in the nanomolar range are considered for further evaluation.This assay was utilized prior to testing using in vivo models. can confirm the inhibitory action of the compound.

Example 4: Human PBMC (CD8+) Assay Human donor blood (8 mL) is collected into sodium citrate CPT tubes and centrifuged at 1,600 xg for 20 minutes at room temperature. The buffy coat containing PBMC is collected and transferred to a 50 mL conical tube containing 30 mL of RPMI-1640 medium (supplemented with penicillin-streptomycin) at room temperature. PBMC samples are centrifuged at 400 xg for 10 minutes at 10°C. Pelleted PBMCs were washed twice in 10 ml of RPMI-1640 medium (supplemented with penicillin-streptomycin) and then RPMI-1640 medium (supplemented with penicillin-streptomycin, fetal bovine serum, and L-glutamine: RPMI-1640 complete medium). PBMC are filtered through a 70 micron mesh to remove cell debris. Adjust the volume to achieve 1.66×10 6 cells/mL, then add 180 μl (300,000 PBMC) to each well in a 96-well plate (sterile, tissue culture treated, round bottom). PBMCs in 96-well plates are placed in a 37° C. 5% CO ₂ incubator for 30 minutes and then subsequently treated with 10 μl of the indicated compounds. For CD8+ (Killing T cell) differentiation assays, PMBC were cultured (1-10×10 ⁴ cells) in RPMI-1640 complete medium for 2, 4, and 6 days and treated with/without AhR antagonist compounds. , 5 uL/ml ImmunoCult™ Human CD3/CD28/CD2 T Cell Activator; Stemcell #10990). Cell viability was measured using a viability dye (eBioscience Fixable Viability Dye eFluor 780: ThermoFisher 65-0865-14) at a 1:500 dilution. Cells were gated on CD8+ defined as Live, CD11c-, CD14-, CD19-, CD8+, CD4-, CD3+. Percent CD8+ (%) was calculated as the percentage of CD8+ cells to total live T cells. Statistical analysis was performed using one-way ANOVA with GraphPad Prism software.

Example 5: Human PBMC Cytokine Assay Human donor blood (8 mL) is collected into sodium citrate CPT tubes and centrifuged at 1,600 xg for 20 minutes at room temperature. The buffy coat containing PBMC is collected and transferred to a 50 mL conical tube containing 30 mL of RPMI-1640 medium (supplemented with penicillin-streptomycin) at room temperature. PBMC samples are centrifuged at 400 xg for 10 minutes at 10°C. Pelleted PBMCs were washed twice in 10 ml of RPMI-1640 medium (supplemented with penicillin-streptomycin) and then RPMI-1640 medium (supplemented with penicillin-streptomycin, fetal bovine serum, and L-glutamine: RPMI-1640 complete medium). PBMC are filtered through a 70 micron mesh to remove cell debris. Adjust the volume to achieve 1.66×10 6 cells/mL, then add 180 μl (300,000 PBMC) to each well in a 96-well plate (sterile, tissue culture treated, round bottom). PBMCs in 96-well plates are placed in a 37° C. 5% CO ₂ incubator for 30 minutes and then subsequently treated with 10 μl of the indicated compounds. For cytokine secretion assays, PMBCs were cultured (1-10×10 4 cells) in RPMI-1640 complete medium for 2, 4, and 6 days and injected with 5 uL/ml ImmunoCult™ with/without AhR antagonist compounds. ) Human CD3/CD28/CD2 T Cell Activator; Stemcell #10990). After 2, 4, and 6 days of incubation at 37° C., 5% CO ₂ , 100 μL of cell supernatant are harvested and transferred to 96-well plates (non-tissue treated, flat bottom). Plates are centrifuged at 350 xg for 5 minutes at room temperature, then cleared supernatants are transferred to new 96-well plates (non-tissue treated, flat bottom). The remaining cells are tested for viability using the CellTiter-Glo® Luminescent Cell Viability Assay (Promega). Supernatants are tested for IL22 and IFg) using Luminex Immunoassay Technology (MAGPIX System). Cytokine levels of PBMC-treated DMSO control samples were set at 100% and compound-treated samples are expressed against this.

Example 6: Solubility Measurement Assay Stock solutions of test and control compound progesterone were prepared in DMSO at a concentration of 10 mM. 15 μL of each sample stock solution (10 mM) was placed in its appropriate 96-well rack in sequence. 485 μL of PBS pH 1.6 and pH 7.4 was added into each vial of the uncapped solubility sample plate. Assays were performed in single replicates. One stir bar was added to each vial and the vials were then sealed using molded PTFE/silicone plugs. The solubility sample plate was then transferred to an Eppendorf Thermomixer Comfort plate shaker and shaken at 1100 rpm for 2 hours at 25°C. After completing the 2 hours, the plug was removed and the stir bar was removed using a large magnet. Samples from the solubility sample plate were transferred to filter plates. All samples were filtered using a Vacuum Manifold. A 5 μL aliquot was taken from the filtrate followed by the addition of a mixture of 495 μL of H2O and acetonitrile (1:1) containing an internal standard. A specific ratio of ultrapure water was used to dilute the dilutions according to the peak shape. Dilution factors were varied according to solubility values and LC-MS signal responses.

From the 10 mM DMSO STD plate, 6 μL was transferred to the remaining empty plate, then 194 μL of DMSO was added to the plate to give an STD concentration of 300 μM. From the 300 μM DMSO STD plate, 5 μL was transferred to the remaining empty plate, then 495 μL of a mixture of HO and acetonitrile (1:1) containing the internal standard was added to the plate to have a final STD concentration of 3 μM. A specific ratio of ultrapure water was used to dilute the dilutions according to peak shape. The concentrations of standard samples were varied according to the LC-MS signal response.

Plates were placed in the wellplate autosampler. Samples were evaluated by LC-MS/MS analysis.

All calculations were performed using Microsoft Excel.

Filtrates were analyzed and quantified against standards of known concentration using LC coupled to mass spectral identification and quantification. Solubility values for test and control compounds were calculated as follows.

Any values for compounds not within the stated limits were eliminated and the experiment repeated.

The solubility of compounds of the present disclosure in pH 1.6 and 7.4 buffers is reported in Table 34. "+++" indicates a solubility value of 1 μM or greater, "++" indicates a solubility value between 0.1 and 1 μM, and "+" indicates a solubility value of less than 0.1 μM.

Example 7: Hepatocyte Stability Assay Preparation of working solutions: 10 mM stock solutions of test compounds and positive controls were prepared in DMSO. In a separate conical tube, 10 mM solutions of test compounds and positive controls were diluted to 100 μM by combining 198 μL of 50% acetonitrile/50% water with 2 μL of 10 mM stock.

Hepatocyte preparation: Incubation medium (William's E medium supplemented with GlutaMAX) and hepatocyte thawing medium were placed in a 37°C water bath and warmed for at least 15 minutes before use. Vials of cryopreserved hepatocytes were removed from storage ensuring that the vials remained at cryogenic temperatures until the thawing process occurred. Cells were thawed by placing the vial in a 37° C. water bath and gently shaking the vial for 2 minutes. After thawing was complete, the vials were sprayed with 70% ethanol and transferred to a safety cabinet. Using a wide-bore pipette tip, hepatocytes were transferred to a 50 mL conical tube containing thawing medium. A 50 mL conical tube was placed in a centrifuge and spun at 100 g for 10 minutes. Once the spin was complete, the thawing medium was aspirated and the hepatocytes were resuspended in sufficient incubation medium to yield approximately 1.5 x ¹⁰⁶ cells/mL. Cells were counted using AO/PI staining to determine viable cell density. Cells with poor viability (<75% viability) were determined to be unacceptable for use. Cells were diluted with incubation medium to a working cell density of 0.5×10 ⁶ viable cells/mL.

Stability measurement procedure: 198 μL of hepatocytes were pipetted into each well of a 96-well uncoated plate. The plate was placed in the incubator to warm the hepatocytes for 10 minutes. 2 μL of 100 μM test compound or positive control solution was pipetted into each well of a 96-well uncoated plate to initiate the reaction. Plates were returned to the incubator at the designated time points. Well contents were transferred to 25 μL aliquots at 0, 15, 30, 60, 90, and 120 minutes. Aliquots were then mixed with 6 volumes (150 μL) of acetonitrile containing an internal standard, IS (100 nM alprazolam, 200 nM caffeine, and 100 nM tolbutamide) to terminate the reaction. The mixture was vortexed for 5 minutes. Samples were centrifuged at 3,220 g for 45 minutes. A 100 μL aliquot of the supernatant was diluted with 100 μL ultrapure water and the mixture was used for LC/MS/MS analysis. All incubations were performed in duplicate.

Data Analysis: All calculations were performed using Microsoft Excel. Peak areas were determined from extracted ion chromatograms. The in vitro half-life (t _1/2 ) of the parent compound was determined by regression analysis of the parent percent elimination versus time curve.

In vitro half-lives (in vitro t _1/2 ) were determined from slope values:
In vitro t _1/2 =0.693/k

Conversion of in vitro t _1/2 (expressed in minutes) to in vitro intrinsic clearance (in vitro CL _int , expressed in μL/min/1×10 ⁶ cells) was performed using the following equation (duplex measurement average):
In vitro CL _int = kV/N
V = incubation volume (0.2 mL);
N=number of hepatocytes per well (0.1×10 ⁶ cells).

Data processing rules: Data processing rules are shown in Table 35.

Human and rat liver hepatocyte clearance of compounds of the present disclosure are reported in Table 36. "+++" indicates a CL _int value less than 20 mL/min/Kg, "++" indicates a CL _{int between 20 and 50 mL/min/Kg, and "+" indicates a CL int greater} than 50 mL/min/Kg.

Example 8: Liver Microsome Stability Assay A master solution was prepared according to Table 37.

Two separate experiments were performed as follows.

With cofactor (NADPH): 25 μL of 10 mM NADPH was added to the incubation. Final concentrations of microsomes and NADPH were 0.5 mg/mL and 1 mM, respectively. The final concentration of microsomes was 0.5 mg/mL. The mixture was pre-warmed at 37°C for 10 minutes. Reactions were initiated by the addition of 2.5 μL of 100 μM control compound or test compound solution. Verapamil was used as a positive control in this study. Final concentrations of test or control compounds were 1 μM. Incubation solutions were incubated in a 37° C. water batch. Aliquots of 25 μL were taken from the reaction solution at 0.5, 5, 15, 30, and 60 minutes. Reactions were stopped by the addition of 5 volumes of cold acetonitrile with IS (200 nM caffeine and 100 nM tolbutamide). Samples were centrifuged at 3,220 g for 40 minutes. A 100 μL aliquot of the supernatant was mixed with 100 μL ultrapure water and then used for LC-MS/MS analysis.

Data Analysis: All calculations were performed using Microsoft Excel. Peak areas were determined from extracted ion chromatograms. The slope value, k, was determined by linear regression of the natural logarithm of the percentage remaining parent drug versus incubation time curve.

In vitro half-lives (in vitro t _1/2 ) were determined from slope values:
In vitro t _1/2 =−(0.693/k)

Conversion of in vitro t _1/2 (min) to in vitro intrinsic clearance (in vitro CL _int , expressed in μL/min/mg protein) was performed using the following equation (average of duplicate measurements):

Calculations of scaled-up CL _int (mL/min/kg), predicted CLH (mL/min/kg) and EH were performed using the following equations:
Scaled-up CL _int = (0.693/t _1/2 ) x (1/(microsomal protein concentration (0.5 mg/mL))) x scaling factor;
predicted CLH = (QH x scaled-up CL _int x f _ub )/(QH + scaled-up CL _int x f _ub );
EH = expected CLH/QH
where QH is liver blood flow (mL/min/kg) (Table 32);
f _ub is the fraction of unbound drug in plasma assumed to be 1;

Scaling factors for intrinsic clearance prediction in human and mouse microsomes are reported in Table 38.

Data processing rules: Data processing rules are shown in Table 39.

Human and rat liver microsomal clearance of compounds of the present disclosure are reported in Table 40. "+++" indicates a Cl _int value less than 10 mL/min/Kg, "++" indicates a Cl _{int between 10 and 20 mL/min/Kg, and "+" indicates a Cl int greater} than 20 mL/min/Kg.

Example 9: Caco-2 Permeability Assay Preparation of Caco-2 cells: 50 μL and 25 mL of cell culture medium were added to each well of the Transwell insert and reservoir, respectively. The HTS transwell plates were incubated at 37° C., 5% CO ₂ for 1 hour before seeding the cells. Caco-2 cells were diluted with medium to 6.86×10 ⁵ cells/mL and 50 μL of cell suspension was dispensed into filter wells of 96-well HTS Transwell plates. Cells were cultured in a cell culture incubator at 37° C., 5% CO ₂ , 95% relative humidity for 14-18 days. Cell culture medium was changed every other day starting within 24 hours of initial seeding.

Assessment of cell monolayer integrity: Media was removed from the reservoir and each Transwell insert and replaced with pre-warmed fresh media. Monolayer transepithelial electrical resistance (TEER) was measured using a Millicell Epithelial Volt-Ohm measurement system (Millipore, USA). Once measurements were taken, the plates were returned to the incubator. TEER values were calculated according to the following equation:
TEER measurement value (ohms) x film area (cm ² ) = TEER value (ohms cm ² )

The TEER value should exceed 230 ohm-cm ² , indicating a suitable Caco-2 monolayer.

Solution preparation: 2 mM stock solutions in DMSO of control compounds were prepared and diluted with HBSS (10 mM HEPES, pH 7.4) to give 10 μM working solutions. A 0.2 mM stock solution of test compound in DMSO was prepared and diluted with HBSS (10 mM HEPES, pH 7.4, containing 0.5% BSA) to give a 1 μM working solution. Metoprolol, erythromycin, and cimetidine were used as control compounds.

Perform drug transport assay: Caco-2 plates were removed from the incubator. Monolayers were washed twice with pre-warmed HBSS (10 mM HEPES, pH 7.4). Plates were incubated for 30 minutes at 37°C. To measure the rate of drug transport in the apical to basolateral direction, 125 μL of working solution was added to the Transwell insert (apical compartment). 50 μL of sample was immediately transferred from the apical compartment to 200 μL of acetonitrile containing IS (100 nM alprazolam, 200 nM caffeine, and 100 nM tolbutamide) in a new 96-well plate as the initial donor sample (AB); It was vortexed at 1000 rpm for 10 minutes. Wells in the receiver plate (basolateral compartment) were filled with 235 μL of transport buffer. To measure the rate of drug transport in the basolateral to apical direction, 285 μL of working solution was added to receiver plate wells (basolateral compartment). 50 μL of sample was immediately transferred from the basolateral compartment to 200 μL of acetonitrile containing IS (100 nM alprazolam, 200 nM caffeine, and 100 nM tolbutamide) in a new 96-well plate as initial donor sample (BA). , which was vortexed at 1000 rpm for 10 minutes. The Transwell insert (apical compartment) was filled with 75 μL of transport buffer. The apical to basolateral and basolateral to apical directions should be performed simultaneously. Plates were incubated for 2 hours at 37°C. At the end of incubation, donor side (apical compartment for Ap→Bl flow and basolateral compartment for Bl→Ap) and receiver side (basolateral compartment for Ap→Bl flow and apical compartment for Bl→Ap). 50 μL samples from were transferred to wells of a new 96-well plate, followed by the addition of 4 volumes of acetonitrile containing IS (100 nM alprazolam, 200 nM caffeine, and 100 nM tolbutamide). Samples were vortexed for 10 minutes and 50 μL samples were transferred to wells of a new 96-well plate followed by the addition of 50 μL Hepes and 200 μL IS. All samples were vortexed for 10 minutes and then centrifuged at 3,220 g for 40 minutes. A 150 μL aliquot of the supernatant was mixed with an appropriate volume of ultrapure water prior to LC-MS/MS analysis.

ここで、Ｉ_{アクセプター}はアクセプターウェル（０．３ｍＬ）中の蛍光強度であり、
Ｉ_ドナーはドナーウェル（０．１ｍＬ）中の蛍光強度であり、漏れ％として表す。 Data Analysis: All calculations were performed using Microsoft Excel. Peak areas were determined from extracted ion chromatograms. The monolayer Lucifer Yellow leakage can be calculated using the following equation:

where I _acceptor is the fluorescence intensity in the acceptor well (0.3 mL),
_Donor I is the fluorescence intensity in the donor well (0.1 mL), expressed as % leakage.

The Lucifer Yellow percentage amount delivered value must be less than 1.5%. However, if the Lucifer Yellow percentage amount transported value for a particular transwell is higher than 1.5, but the measured digoxin P _app in that transwell is qualitatively similar to that measured in the repeat transwell. , the monolayer is considered acceptable based on the scientific judgment of the responsible scientist.

ここで、Ｐ_ａｐｐは見かけの透過性（ｃｍ／ｓ×１０^－６）であり；
ｄＱ／ｄｔは薬物輸送の速度（ｐｍｏｌ／秒）であり；
Ａは膜の表面積（ｃｍ２）であり；
Ｄ_ｏは初期ドナー濃度（ｎＭ；ｐｍｏｌ／ｃｍ_３）である。 Apparent permeability (P _app ) can be calculated for drug transport assays using the following equation:

where P _app is the apparent permeability (cm/s×10 ⁻⁶ );
dQ/dt is the rate of drug transport (pmol/sec);
A is the surface area of the membrane (cm2);
D _o is the initial donor concentration (nM; pmol/cm ₃ ).

ここで、Ｐ_{ａｐｐ（Ｂ－Ａ）}は側底側から頂端側方向の見かけの透過係数を示し、
Ｐ_{ａｐｐ（Ａ－Ｂ）}は頂端側から側底側方向への見かけの透過係数を示す。 Elimination ratio can be determined using the following equation:

where P _{app (B−A)} is the apparent permeability coefficient in the basolateral to apical direction,
P _{app (AB)} indicates the apparent permeability coefficient in the apical to basolateral direction.

Apparent permeability ratios for compounds of the present disclosure are reported in Table 41. “A” indicates a P _app value greater than 10×10 ⁻⁶ cm/sec, “B” indicates a P app between 2 and 10×10 ⁻⁶ cm/sec, and “C” indicates a P _app value of 2×10 ⁻⁶ cm/sec. / _sec .

Example 10 Plasma Protein Binding Measurements by Ultracentrifugation Frozen plasma (stored at −80° C.) was thawed in a 37° C. water bath followed by centrifugation at 3,220 g for 10 minutes to remove clots. . The supernatant was removed and placed as spun plasma in a new tube. The centrifuged plasma was prewarmed in a 37°C water bath for 10 minutes. Stock solutions of test compounds were diluted in DMSO to 200 μM and then spiked into plasma. Duplicate samples were prepared. The final concentration of compound was 1.0 μM. The final concentration of organic solvent was 0.5%. Warfarin was used as a positive control in the assay. 1.0 mL of spiked plasma was transferred to a new balanced ultracentrifuge tube. Samples were incubated at 37° C., 5% CO ₂ for 30 minutes. After incubation, the balance ultracentrifuge tubes were centrifuged at 600,000 g for 5.5 hours at 37°C. After centrifugation, 50 μL solution was removed from the center of the ultracentrifuge tube as the post-ultracentrifugation sample, followed by 50 μL blank plasma and 400 μL quench solution (internal standards (IS, 100 nM alprazolam, 500 nM labetalol, and 2 μM ketoprofen). Acetonitrile containing ) was added to precipitate the protein and release the compound. Samples were vortexed for 2 minutes followed by centrifugation at 20,000 g for 15 minutes at room temperature. The supernatant was diluted with ultrapure water and then used for LC-MS/MS analysis. Stability samples were prepared by transferring 50 μL of spiked plasma to 0.6 mL tubes and incubated at 37° C., 5% CO ₂ for 0.5 and 6 hours. After incubation, 50 μL of PBS (100 mM, pH 7.4) and 400 μL of quench solution were used for stability samples. The stability samples were then treated similarly to the post-ultracentrifugation samples. The supernatant was diluted with ultrapure water and then used for LC-MS/MS analysis. A 0.5 hour time point sample was also used as a no-spun control. Time 0 samples were prepared by transferring 50 μL of spiked plasma to a 0.6 mL tube containing 50 μL of PBS, followed by the addition of 400 μL of quench solution to precipitate proteins and release compounds. . These samples were then treated similarly to the post-ultracentrifugation samples. The supernatant was diluted with ultrapure water and then used for LC-MS/MS analysis.

Data Analysis: All calculations were performed using Microsoft Excel. Concentrations of test compounds in plasma samples and plasma after ultracentrifugation were determined from peak areas. The percentage of bound test compound was calculated as follows:
% unbound = (Peak area after ultracentrifugation/Peak area of uncentrifuged control) x 100%
% Bound = 100% - % Unbound
% Remaining at 0.5 hours = peak area at 0.5 hours/peak area at 0 hours x 100%
% Remaining at 6 hours = peak area at 6 hours/peak area at 0 hours x 100%

The levels of binding of compounds of the present disclosure to human, rat and mouse plasma proteins are reported in Table 42. "+++" indicates a % Bound value less than 50, "++" indicates a % Bound value between 50 and 75, and "+" indicates a % Bound value greater than 75.

Example 11: CYP Inhibition Assay Stock solutions of test compounds were prepared in DMSO at a concentration of 10 mM. Stock solutions were diluted to 2 mM with acetonitrile. The final concentration of test compound was 10 μM. Concentrations of positive inhibitors are listed in Table 43. For stock solution preparation, if the positive control was not sufficiently soluble in a mixture of DMSO and acetonitrile (1:4) at the highest concentration, another mixture of acetonitrile and DMSO, acetonitrile and HO or DMSO was added. , will be used to dissolve the compound.

Preparation details for these substrates are given in Table 44. Store the substrate solution in a −20° C. freezer and warm to room temperature before use.

Preparation of phosphate buffer (100 mmol/L, pH 7.4): To prepare solution A, weigh 7.098 g of disodium hydrogen phosphate, add to 500 mL of pure water, and then sonicate. The contents were allowed to dissolve. To prepare solution B, 3.400 g of potassium dihydrogen phosphate was weighed, added to 250 mL of pure water, and then sonicated to dissolve the contents. Solution A was placed on a stirrer and solution B was slowly added to solution A until the pH reached 7.4. Preparation of 10 mmol/L NADPH solution: NADPH was dissolved in phosphate buffer at 8.334 mg/mL; solution was freshly prepared before use.

A master solution was prepared according to Table 45. Incubation was performed in 96 deep well plates. The following volumes were dispensed into each well of the incubation plate: 179 μL of substrate and HLM mixture in phosphate buffer, 1 μL of compound working solution, or vehicle (mixture of DMSO and acetonitrile (1:4)). The incubation plate was placed in a water bath and pre-warmed at 37° C. for 15 minutes before the reaction was initiated by the addition of 20 μL of 10 mmol/L NADPH in phosphate buffer. After addition of NADPH, incubation plates were incubated at 37° C. for the corresponding time. Assays were performed in duplicate.

Reactions were quenched by the addition of 1.5 volumes (300 μL) of cold acetonitrile containing 3% formic acid and internal standards (200 nM labetalol, 200 nM alprazolam, and 200 nM tolbutamide). Plates were centrifuged at 3,220 g for 40 minutes. 100 μL of supernatant was transferred to a new plate. The supernatant was diluted with 100 μL pure water. Samples were mixed well and analyzed using UPLC/MS/MS.

Data Analysis: Automatic peak integration areas are checked for all samples. Export the analyte peak areas and internal standard peak areas to an excel spreadsheet. Inhibition of each P450 enzyme in human liver microsomes is measured as a percentage decrease in activity of marker metabolite formation compared to uninhibited controls (=100% activity).

The percentage of remaining activity was calculated as follows:
Area ratio = Peak area of analyte/Peak area of internal standard Residual activity (%) = Area ratio of test compound/Area ratio of vehicle x 100%
% inhibition = 100 - residual activity (%)

The % inhibition of CYP2D6 and CYP3A4 for compounds of the present disclosure is reported in Table 46.

Example 12: hERG Inhibition Assay A stably expressed hERG HEK 293 cell line (catalog number K1236) was purchased from Invitrogen. Cells are cultured in 85% DMEM, 10% dialyzed FBS, 0.1 mM NEAA, 25 mM HEPES, 100 U/mL penicillin-streptomycin, and 5 μg/mL blasticidin and 400 μg/mL geneticin. Cells are split approximately three times per week using TrypLE™ Express and maintained at approximately 40% to approximately 80% confluence. Prior to assay, cells were on coverslips at 5 x 105 cells per 6 cm cell culture dish and induced with 1 μg/mL doxycycline for 48 hours.

External solution (in mM): 132 NaCl, 4 KCl, 3 CaCl2, 0.5 MgCl2, 11.1 glucose and 10 HEPES (adjusted to pH 7.35 with NaOH). Internal solution (in mM): 140 KCl, 2 MgCl2, 10 EGTA, 10 HEPES and 5 MgATP (adjusted to pH 7.35 with KOH). Working solution preparation of test compounds: Test compounds were initially prepared as stock solutions in DMSO at a final concentration of 10 mM. Each compound stock solution was serially diluted in DMSO at a 1:3 ratio to prepare three additional intermediate solutions containing 3.33, 1.11, and 0.37 mM.

10, 3.33, 10, 3.33, 10, 3.33, 10, 3.33, 10, 3.33, 10, 3.33, 10, 3.33, 10, 3.33, 10, 3.33, 3.33, 3.33, 3.33, 3.33, 3.33, 3.33, 3.33, 3.33, 3.33, 3.33, 3.33, 3.33, using extracellular solution, such that the final concentrations of the working solutions are 30, 10, 3.33, 1.11, and 0.37 μM prior to performing the hERG assay. Working solutions were prepared by 1000-fold dilutions of 1.11 and 0.37 mM intermediate solutions, while 30 μM working solutions were prepared by 333.333-fold dilutions of 10 mM DMSO stocks. The final DMSO concentration in the working solution was kept in the range of 0.1-0.3% (v/v).

Experimental procedure: Remove the coverslip from the cell culture dish and place it on the microscope stage in the bath chamber. Desired cells were found using a 10x objective. The tip of the electrode was found under the microscope by focusing on the plane of the cell using a 10x objective. Once the tip was in focus, the electrode was advanced down toward the cell using the coarse adjustment of the manipulator while moving the objective lens to keep the tip in focus. When directly over the cell, fine adjustment of the manipulator was used to gradually approach the surface of the cell by using a 40x objective. Gentle suction was applied to the side port of the electrode holder to form a gigaohm seal.

Cfast was used to remove the capacity current coinciding with the voltage step. A whole-cell configuration was obtained by repeatedly applying short bursts of strong suction until the membrane patch ruptured. The membrane potential was set at -60 mV at this time to ensure that the hERG channel was not open. The capacitive current spike was then canceled by using the Cslow of the amplifier.

The holding potential was set to −90 mV for 500 ms; currents were recorded at 20 kHz and filtered at 10 kHz. Leakage current was tested at −80 mV for 500 ms.

hERG currents were evoked by depolarizing at +30 mV for 4.8 seconds, then the voltage was returned to −50 mV for 5.2 seconds to remove deactivation and observe a deactivating tail current. The maximal tail current size was used to determine the hERG current amplitude. Currents were recorded for 120 seconds to assess current stability. Only stable cells with recording parameters exceeding the threshold were advanced for further drug administration. A vehicle control was applied to the cells to establish a baseline. Once the hERG current was found to be stable for 5 minutes, the working solution was applied. hERG currents in the presence of test compounds were recorded for approximately 5 minutes to reach steady state and then 5 sweeps were acquired. For dose-response studies, five doses of test compound were applied to the cells, increasing from low to high concentrations. A positive control dofetilide at five doses was also used in testing the same batch of cells to ensure good performance of the cultured cells and manipulations.

Data validity was determined using the following criteria: initial seal resistance >1 GΩ; leakage current <50% of control peak tail current at all times; peak tail amplitude >300 pA; membrane resistance Rm >500 MΩ; ) < 15 MΩ; apparent decay of peak current < 2.5% per minute.

Data meeting the above criteria for hERG current quality were further analyzed as per the following steps. Percent current inhibition was calculated using the following equation: (Note: Peak currents were extracted from the original data using PatchMaster or Clampfit software).

Test compound dose-response curves were plotted by % inhibition against test compound concentration using GraphPad Prism 6.0, and data were fitted to a sigmoidal dose-response curve with variable slope.

_IC50s for compounds of the present disclosure are reported in Table 47.

Example 13: In Vivo Rat PK Studies Studies were performed in male Sprague-Dawley rats, 3 rats per group, or in male CD1 mice, 3 mice per group. Compounds were administered intravenously at 1.0 mg/Kg (vehicle ethanol:% PEG 400 in deionized water, in ratios suitable for clear solution dosing) and orally at 3.0 mg/kg or 10 mg/kg (vehicle: 1 % methylcellulose: 1,500 cP (w/v) in deionized water) was administered. All animals had free access to food and water. Rat intravenous PK time points: plasma: 0.083, 0.25, 0.5, 1, 2, 4, 8, and 24 hours; rat oral PK time points: plasma: 0.25, 0.5, 1, 2 , 4, 8, and 24 hours. Mouse intravenous PK time points: plasma: 0.083, 0.25, 0.5, 1, 2, 4, 8, 24, and 48 hours; mouse oral PK time points: plasma: 0.25, 0.5, 1 , 2, 4, 8, 24, and 48 hours. Concentrations of compounds in plasma samples were analyzed using an LC-MS/MS method. WinNonlin (Phoenix™, version 6.1) or other similar software was used for pharmacokinetic calculations.

Mouse and Rat PK Study Data Pharmacokinetic data are shown in Tables 48-51 below. PK data for mice that received 1 mg/mL IV of a compound of the present disclosure are reported in Table 48. PK data for mice administered 10 mg/mL PO of compounds of the present disclosure are reported in Table 49. PK data for rats dosed with 1 mg/mL IV of compounds of the present disclosure are reported in Table 50. PK data for rats dosed with 3 or 10 mg/mL PO of compounds of the present disclosure are reported in Table 51.

AHR Antagonist and Checkpoint Inhibitor Anti-PD-1 Efficacy Testing in Mouse Colon Cancer Model CT26 in In Vivo Model Balb/c Mice Female mice aged 6-8 weeks were obtained from the Charles River Laboratory (C57BL/6NCrl). Mouse tumor cell line WT-CT26 was obtained from the American Type Culture Collection, tested for mycoplasma and other pathogens at Charles River Research Animal Diagnostics services, and cultured according to their guidelines. All tests were conducted in accordance with the CRADL Policy on the Care, Welfare and Treatment of Laboratory Animals. From the day of tumor inoculation, mice were monitored a minimum of three times weekly by the investigator or veterinary staff for clinical abnormalities that may require euthanasia. These include chronic and/or severe diarrhea resulting in moderate to severe dehydration, evidence of infection that is not easily treatable, debilitating or dyslexia in conjunction with other clinical signs if prolonged for more than 3 days. Posture, inability/unwillingness to ambulate to reach food or water, or other clinical signs judged by experienced technical staff to indicate morbidity or moribundity. Mice exhibiting a net weight loss greater than 20% compared to baseline body weight measurements were euthanized.

CT26 is a murine colon cancer cell line obtained from ATCC. CT26 cells were cultured in RPMI supplemented with 10% FBS. Low passage CT26 cells were resuspended in 100 μL PBS at 5×10 ⁵ cells/ml and implanted subcutaneously into the shaved lower right flank of 6-8 week old Balb/c mice. The day of subcutaneous tumor cell implantation was defined as day 0.

Once the entry criteria were met, animals were distributed into treatment groups such that the mean tumor burden in each group was within 10% of the overall mean. Mice were dosed individually by body weight on the day of treatment.

One week after inoculation, mice bearing tumors with an average size of approximately 60 mm ³ were randomized and made available to begin treatment (Fig. 1). AhR antagonists were administered orally daily (QD) at 1 mg/kg, 3 mg/kg, or 10 mg/kg for 14 days. Anti-PD-1 (BioXcell RMP1-14) or anti-PD-L1 was administered intraperitoneally starting on day 14 at 100 μg/kg every 3 days for 3 doses.

Tumors were monitored by perpendicular tumor diameter measurements, calculated daily by caliper measurements using the formula (mm ³ )=0.52×(length)×(width) ² , and body weights were measured three times weekly. . At endpoint, tumors were harvested and analyzed for infiltrating tumor immune cells by flow cytometry and/or IHC.

AHR-Dependent Gene Expression in Tumor, Spleen and Liver AHR-dependent gene expression will be measured in tissue samples such as tumor or liver. RNA will be extracted from the tissue with an RNA isolation kit such as Qiagen. RNA extraction may be performed from whole cells or cells after sorting of specific cell populations such as tumor cells, tumor-associated T-cells, tumor-associated bone marrow cells, tumor-associated macrophages, or others. Gene expression will be determined by quantitative RT-PCR using specific gene probes, including housekeeping genes such as Gapdh for normalization. AHR-dependent genes that may be investigated include, but are not limited to, CYP1A1, CYP1B1, AHRR, IDO1, IDO2, IL22, IL6, VEGFA, STAT3, cdc2, MMP13, MMP-9.

Example 14: Drug Metabolism and Pharmacokinetic Profiles of Compounds #9 and #46 Compounds #9 and #46 have the following in vitro DMPK profiles.

Compounds #9 and #46 have the following in vivo DMPK profiles.

A plot of mean plasma concentrations of Compound #46 over time after 1 mg/kg IV and 10 mg/kg PO in CD1 mice is shown in FIG. A plot of mean plasma concentrations of Compound #46 over time after 1 mg/kg IV and 3 mg/kg PO in SD rats is shown in FIG.

A plot of mean plasma concentrations of Compound #9 over time after 1 mg/kg IV and 10 mg/kg PO in CD1 mice is shown in FIG. A plot of mean plasma concentrations of Compound #9 over time after 1 mg/kg IV and 3 mg/kg PO in SD rats is shown in FIG.

Example 15 Combination Therapy with Immune Checkpoint Inhibitors (ICIs) Aromatic hydrocarbon receptors antagonized the activity of tryptophan metabolites alone or in combination with checkpoint inhibitors (ICIs) for multiple types of cancer A study was conducted to identify potent and selective low-dose modulators of

Anti-tumor efficacy of compound #7 in the CT26 syngeneic model. CT26 cells were implanted subcutaneously into Balb/c mice, then mice were randomized to be treated with either PD-L1 antibody alone or PD-L1 antibody in combination with Compound #7. Compound #7 was administered orally once daily at 3 mg/kg for 14 days of dosing in combination with anti-PD-L1 antibody administered intraperitoneally at 10 mg/kg every 3 days. Tumor growth curves of vehicle versus single agent PD-L1 antibody or PD-L1 antibody together with Compound #7 are shown in FIG. Co-administration of Compound #7 and PD-L1 antibody showed a decrease in tumor volume, p=0.0039 (Mann-Whitney, non-parametric test). Also shown in FIG. 3 are tumor weights at the end of the study of vehicle versus single agent PD-L1 antibody or PD-L1 antibody with Compound #7. Co-administration of Compound #7 and PD-L1 antibody showed a decrease in tumor weight, p=0.041 (Mann-Whitney, non-parametric test).

Anti-tumor efficacy of compound #30 in the CT26 syngeneic model. CT26 cells were implanted subcutaneously into Balb/c mice, then mice were randomized and treated with either Compound #30 alone, PD-L1 antibody alone, or PD-L1 antibody in combination with Compound #30. Compound #30 was administered orally once daily at 10 mg/kg for 14 days of dosing in combination with anti-PD-L1 antibody administered intraperitoneally at 10 mg/kg every 3 days. Tumor growth curves of vehicle versus single agent PD-L1 antibody or Compound #30 alone or PD-L1 antibody together with Compound #30 are shown in FIGS. Co-administration of Compound #30 and PD-L1 antibody showed a decrease in tumor volume, p=0.039 (FIG. 4, Mann-Whitney, non-parametric test) and p=0.350 (FIG. 6, Kruskal • Wallis test followed by nonparametric Dunn's multiple comparison test). Also shown in FIGS. 5 and 7 are tumor weights at the end of the study of vehicle versus single agent PD-L1 antibody, or Compound #30 alone or PD-L1 antibody together with Compound #30. Co-administration of Compound #30 and PD-L1 antibody showed a decrease in tumor weight, p=0.067 (FIG. 5, Mann-Whitney, non-parametric test) and p=0.0004 (FIG. 7, Kruskal). • Wallis test followed by nonparametric Dunn's multiple comparison test).

Anti-tumor efficacy of compound #9 in the CT26 syngeneic model. CT26 cells were implanted subcutaneously into Balb/c mice, then mice were randomized and treated with either compound #9 alone, PD-L1 antibody alone, or PD-L1 antibody in combination with compound #9. Compound #9 was administered orally at 10 mg/kg (Figure 8) or 1 mg/kg (Figure 10) for 14 days of combined dosing with an anti-PD-L1 antibody administered intraperitoneally at 10 mg/kg every 3 days. Dosing was once daily. Tumor growth curves of vehicle versus single agent PD-L1 antibody or Compound #9 alone or PD-L1 antibody together with Compound #9 are shown in FIGS. Co-administration of Compound #9 and PD-L1 antibody showed a decrease in tumor volume, p=0.0070 (FIG. 8, Mann-Whitney, non-parametric test) and p=0.0039 (FIG. 10, Kruskal • Wallis test followed by nonparametric Dunn's multiple comparison test). Also shown in FIGS. 9 and 11 are tumor weights at the end of the study of vehicle versus single agent PD-L1 antibody or compound #9 alone or PD-L1 antibody together with compound #9. Co-administration of Compound #9 and PD-L1 antibody showed a decrease in tumor weight, p=0.0114 (FIG. 9, Mann-Whitney, non-parametric test) and p=0.0029 (FIG. 11, Kruskal • Wallis test followed by nonparametric Dunn's multiple comparison test). Overall, Compound #9 in combination with PD-L1 reduces tumor volume and weight compared to PD-L1 alone.

Anti-tumor efficacy of compound #46 in the CT26 syngeneic model. CT26 cells were implanted subcutaneously into Balb/c mice, then mice were randomized and treated with either Compound #46 alone, PD-L1 antibody alone, or PD-L1 antibody in combination with Compound #46. Compound #46 was administered orally once daily at 10 mg/kg for 14 days of dosing in combination with anti-PD-L1 antibody administered intraperitoneally at 10 mg/kg every 3 days. Tumor growth curves for vehicle versus single agent PD-L1 antibody or compound #46 alone or in combination with compound #46 are shown in FIG. Co-administration of Compound #46 and PD-L1 antibody showed a decrease in tumor volume. Also shown in FIG. 13 are tumor weights at the end of the study of vehicle versus single agent PD-L1 antibody or Compound #46 alone or PD-L1 antibody together with Compound #46. Co-administration of compound #46 and PD-L1 antibody showed a decrease in tumor weight.

Claims (76)

Compounds of Formula I:

and a pharmaceutically acceptable salt thereof (wherein:
each of R ¹ and R ² is optionally substituted alkyl, optionally substituted ester, optionally substituted heteroalkyl, optionally substituted acyl, optionally substituted amide, independently selected from optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted amine, and optionally substituted heterocycloalkyl; and R ³ is hydrogen, optionally substituted alkyl, optionally substituted acyl, optionally substituted amido, optionally substituted aryl, optionally substituted cycloalkyl, optionally optionally substituted heteroalkyl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, optionally substituted amine, cyano, halo, hydroxy, and — C(O)H). Compounds of Formula Ia

or a pharmaceutically acceptable salt thereof (wherein:
Ring A is selected from optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, and optionally substituted heterocycloalkyl;
Ring B is selected from optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, and optionally substituted heterocycloalkyl; and R is hydrogen; optionally substituted alkyl, optionally substituted acyl, optionally substituted amide, optionally substituted aryl, optionally substituted cycloalkyl, optionally substituted ester, optional optionally substituted heteroalkyl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, amino, cyano, halo, hydroxy, and -C(O)H). Ring A is optionally substituted 6-10 membered aryl, optionally substituted 5-10 membered heteroaryl, optionally substituted 3-10 membered cycloalkyl, and optionally substituted 3 is selected from -10 membered heterocycloalkyl;
Ring B is optionally substituted 6-10 membered aryl, optionally substituted 5-10 membered heteroaryl, optionally substituted 3-10 membered cycloalkyl, and optionally substituted 3 is selected from -10 membered heterocycloalkyl;
R is hydrogen, optionally substituted C ₁ -C ₁₀ alkyl, optionally substituted 6-10 membered aryl, —C(O)R′, —C(O)NR′R′, optionally 3-10 membered cycloalkyl substituted with, —C(O)OR′, optionally substituted C ₁ -C ₁₀ heteroalkyl, optionally substituted 5-10 membered heteroaryl, optionally substituted 3-10 membered heterocycloalkyl, amino, cyano, halo, hydroxy, and —C(O)H; and each R′ is hydrogen, optionally substituted C ₁ -C ₁₀ alkyl, and optionally substituted C ₁ -C ₁₀ heteroalkyl, or a pharmaceutically acceptable salt thereof, according to claim 2. Ring A is selected from 6-10 membered aryl, 5-10 membered heteroaryl, 3-10 membered cycloalkyl, and 3-10 membered heterocycloalkyl, each of which is 6-10 membered aryl, 5-10 membered heteroaryl, 3-10 membered cycloalkyl, and 3-10 membered heterocycloalkyl are optionally substituted independently with 1-5 instances of R ^A ;
ring B is selected from 6-10 membered aryl, 5-10 membered heteroaryl, 3-10 membered cycloalkyl, and 3-10 membered heterocycloalkyl, each of 6-10 membered aryl, 5-10 membered heteroaryl, 3-10 membered cycloalkyl, and 3-10 membered heterocycloalkyl are optionally substituted independently with 1-5 instances of R ^B ;
R is hydrogen, C ₁ -C ₁₀ alkyl, 6-10 membered aryl, —C(O)R′, —C(O)NR′R′, 3-10 membered cycloalkyl, —C(O)OR′ , C ₁ -C ₁₀ heteroalkyl, 5-10 membered heteroaryl, 3-10 membered heterocycloalkyl, amino, cyano, halo, hydroxy, and —C(O)H, each C ₁ -C ₁₀ alkyl , 6- to 10-membered aryl, 3- to 10-membered cycloalkyl, C ₁ -C ₁₀ heteroalkyl, 5- to 10-membered heteroaryl, and 3- to 10-membered heterocycloalkyl are independently optional with 1-5 instances of R 1 ^C is replaced by a selection;
each R′ is independently selected from hydrogen, C ₁ -C ₁₀ alkyl, C ₁ -C ₁₀ haloalkyl, C ₁ -C ₁₀ hydroxyalkyl, and C ₁ -C ₁₀ heteroalkyl;
Each R ^A is halo, hydroxy, C ₁ -C ₁₀ alkyl, C ₁ -C ₁₀ haloalkyl, C ₁ -C ₁₀ alkoxy, C ₁ -C ₁₀ haloalkoxy, C ₁ -C ₁₀ hydroxyalkyl, and NR″ independently selected from R'';
Each R ^B is halo, hydroxy, C ₁ -C ₁₀ alkyl, C ₁ -C ₁₀ haloalkyl, C ₁ -C ₁₀ alkoxy, C ₁ -C ₁₀ haloalkoxy, C ₁ -C ₁₀ hydroxyalkyl, and NR″ independently selected from R'';
Each R ^C is halo, hydroxy, cyano, C ₁ -C ₁₀ alkyl, C ₁ -C ₁₀ alkoxy, C ₁ -C ₁₀ haloalkyl, 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, 6-10 independently selected from 5- to 10-membered heteroaryl; and each R″ is hydrogen, C ₁ -C ₁₀ alkyl, C ₁ -C ₁₀ haloalkyl, C ₁ -C ₁₀ hydroxyalkyl, and C ₁ 4. The compound of claim 2 or 3, or a pharmaceutically acceptable salt thereof, independently selected from _{-C10heteroalkyl} . 5. The compound of claim 4, or a pharmaceutically acceptable salt thereof, wherein ring A is selected from 3-10 membered cycloalkyl optionally substituted with 1-5 instances of R 1 ^A. 6. A compound according to claims 4 or 5, or a pharmaceutical thereof, wherein ring A is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl optionally substituted with 1 to 5 instances of R ^A acceptable salt. 5. The compound of claim 4, or a pharmaceutically acceptable salt thereof, wherein ring A is selected from 6-8 membered aryl optionally substituted with 1-5 instances of R 1 ^A. 8. The compound of claim 4 or 7, or a pharmaceutically acceptable salt thereof, wherein ring A is phenyl optionally substituted with 1-3 instances of R 1 ^A. 5. The compound of claim 4, or a pharmaceutically acceptable salt thereof, wherein ring A is selected from 5-8 membered heteroaryl optionally substituted with 1-5 instances of R 1 ^A. Ring A is selected from pyrrolyl, furanyl, furazanyl, thiophenyl, imidazolyl, isothiazolyl, isoxazolyl, oxazolyl, oxadiazolyl, tetrazolyl, thiazolyl, triazolyl, pyrazolyl, pyridinyl, pyrazinyl, pyridazinyl, and pyrimidinyl;
pyrrolyl, furanyl, furazanyl, thiophenyl, imidazolyl, isothiazolyl, isoxazolyl, oxazolyl, oxadiazolyl, tetrazolyl, thiazolyl, triazolyl, pyrazolyl, pyridinyl, pyrazinyl, pyridazinyl, and pyrimidinyl each independently optional with 1-3 instances of R ^A 10. The compound of claim 4 or 9, or a pharmaceutically acceptable salt thereof, which is substituted with 11. The compound of any one of claims 4, 9 and 10, or a pharmaceutically acceptable salt thereof, wherein ring A is pyridinyl optionally substituted with 1-3 instances of R 1 ^A. 5. The compound of claim 4, or a pharmaceutically acceptable salt thereof, wherein ring A is selected from 5-8 membered heterocycloalkyl optionally substituted with 1-5 instances of R 1 ^A. Ring A is selected from pyrrolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, morpholino, azepinyl, tetrahydropyranyl, and tetrahydrofuranyl;
13. The compound of claim 4 or 12, wherein each of pyrrolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, morpholino, azepinyl, tetrahydropyranyl, and tetrahydrofuranyl is independently optionally substituted with 1-3 instances of ^RA . or a pharmaceutically acceptable salt thereof. 14. The compound of any one of claims 4, 12 and 13, or a pharmaceutically acceptable salt thereof, wherein ring A is piperidinyl or morpholino optionally substituted with 1-3 instances of R 1 ^A. 5. The compound of claim 4, or a pharmaceutically acceptable salt thereof, wherein ring B is selected from 6-8 membered aryl optionally substituted with 1-5 instances of R 1 ^B. 16. The compound of claim 4 or 15, or a pharmaceutically acceptable salt thereof, wherein ring B is phenyl optionally substituted with 1-3 instances of R 1 ^B. 5. The compound of claim 4, or a pharmaceutically acceptable salt thereof, wherein ring B is selected from benzodioxolyl and 5-8 membered heteroaryl optionally substituted with 1-5 instances of R 1 ^B. Ring B is selected from benzodioxolyl, pyrrolyl, furanyl, furazanyl, thiophenyl, imidazolyl, isothiazolyl, isoxazolyl, oxazolyl, oxadiazolyl, tetrazolyl, thiazolyl, triazolyl, pyrazolyl, pyridinyl, pyrazinyl, pyridazinyl, pyridinonyl, and pyrimidinyl;
benzodioxolyl, pyrrolyl, furanyl, furazanyl, thiophenyl, imidazolyl, isothiazolyl, isoxazolyl, oxazolyl, oxadiazolyl, tetrazolyl, thiazolyl, triazolyl, pyrazolyl, pyridinyl, pyrazinyl, pyridazinyl, and pyrimidinyl each represents one to three instances of R ^B 18. The compound of claim 4 or 17, or a pharmaceutically acceptable salt thereof, optionally substituted independently by. Ring B is selected from pyrazolyl, isothiazolyl, isoxazolyl, pyridinyl, pyrimidinyl, and thiophenyl;
19. Any one of claims 4, 17 and 18, wherein each of pyrazolyl, isothiazolyl, isoxazolyl, pyridinyl, pyrimidinyl, and thiophenyl is independently optionally substituted with 1-3 instances of R ^B A compound or a pharmaceutically acceptable salt thereof. each R ^A is independently selected from halo, C ₁ -C ₁₀ alkyl, C ₁ -C ₁₀ haloalkyl, C ₁ -C ₁₀ alkoxy, C ₁ -C ₁₀ haloalkoxy, and NR″R″;
each R ^B is independently selected from halo, C ₁ -C ₁₀ alkyl, and C ₁ -C ₁₀ haloalkyl;
each R ^C is independently selected from halo, hydroxy, cyano, C ₁ -C ₁₀ alkyl, C ₁ -C ₁₀ alkoxy, 3-8 membered cycloalkyl, 3-8 membered heterocycloalkyl, and 6-8 membered aryl and each R″ is independently selected from hydrogen and C ₁ -C ₁₀ alkyl, or a pharmaceutically acceptable salt thereof, according to any one of claims 4-19. Ring A is

A compound according to any one of claims 2-4 and 7-20, or a pharmaceutically acceptable salt thereof, selected from: Ring A is

A compound according to any one of claims 2-6 and 15-20, or a pharmaceutically acceptable salt thereof, selected from: Ring A is

A compound according to any one of claims 2-4 and 7-20, or a pharmaceutically acceptable salt thereof, selected from: Ring B is

A compound according to any one of claims 2-4 and 7-20, or a pharmaceutically acceptable salt thereof, selected from: Ring B is

A compound according to any one of claims 2-14 and 20, or a pharmaceutically acceptable salt thereof, selected from: Ring B is

A compound according to any one of claims 2-4 and 7-20, or a pharmaceutically acceptable salt thereof, selected from: R is methyl;

A compound according to any one of claims 2 to 26, or a pharmaceutically acceptable salt thereof, selected from: R is methyl;

A compound according to any one of claims 2 to 27, or a pharmaceutically acceptable salt thereof, selected from: At least one entity selected from the following compounds and pharmaceutically acceptable salts thereof:
(i) (S)-8-(5-fluoropyridin-3-yl)-3-(1-hydroxypropan-2-yl)-6-(4-(trifluoromethoxy)phenyl)pyrido[3,4 -d]pyrimidin-4(3H)-one;
(ii) (S)-6-(4-chlorophenyl)-3-(1-hydroxypropan-2-yl)-8-(6-oxo-1,6-dihydropyridin-3-yl)pyrido[3,4 -d]pyrimidin-4(3H)-one;
(iii) (S)-8-(benzo[d][1,3]dioxol-4-yl)-6-(4-chlorophenyl)-3-(1-hydroxypropan-2-yl)pyrido[3, 4-d]pyrimidin-4(3H)-one;
(iv) (S)-3-(1-hydroxypropan-2-yl)-8-(pyridin-4-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido [3, 4-d]pyrimidin-4(3H)-one;
(v) (S)-8-(5-fluoropyridin-3-yl)-3-(1-hydroxypropan-2-yl)-6-(4-(trifluoromethyl)phenyl)pyrido[3,4 -d]pyrimidin-4(3H)-one;
(vi) (S)-3-(1-hydroxypropan-2-yl)-6,8-di(pyridin-4-yl)pyrido[3,4-d]pyrimidin-4(3H)-one;
(vii) (S)-6-(4-chlorophenyl)-8-(3-fluorophenyl)-3-(1-hydroxypropan-2-yl)pyrido[3,4-d]pyrimidine-4(3H) -on;
(viii) (S)-8-(3-fluorophenyl)-3-(1-hydroxypropan-2-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4 -d]pyrimidin-4(3H)-one;
(ix) 3-(2-hydroxy-2-methylpropyl)-8-(pyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d] pyrimidin-4(3H)-one;
(x) 6,8-di(pyridin-3-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)pyrido[3,4-d]pyrimidin-4(3H)-one;
(xi) (S)-6-chloro-3-(1-hydroxypropan-2-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one;
(xii) (S)-3-(1-hydroxypropan-2-yl)-8-(pyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido [3, 4-d]pyrimidin-4(3H)-one;
(xiii) 6-(4-chlorophenyl)-8-(pyridin-3-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)pyrido[3,4-d]pyrimidine-4 ( 3H)—on;
(xiv) 8-(pyridin-3-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)-6-(4-(trifluoromethoxy)phenyl)pyrido[3,4-d ] pyrimidin-4(3H)-one;
(xv) 6-(4-chlorophenyl)-8-(1-methyl-1H-pyrazol-4-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)pyrido[3,4- d] pyrimidin-4(3H)-one;
(xvi) 3-(2-hydroxy-2-methylpropyl)-8-(pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyrimidine-4 ( 3H)—on;
(xvii) (S)-3-(1-hydroxypropan-2-yl)-8-(pyridin-3-yl)-6-(p-tolyl)pyrido[3,4-d]pyrimidine-4(3H )-on;
(xviii) 6-(4-chlorophenyl)-3-(2-hydroxy-2-methylpropyl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one;
(xix) 3-(2-hydroxy-2-methylpropyl)-6,8-bis(1-methyl-1H-pyrazol-4-yl)pyrido[3,4-d]pyrimidin-4(3H)-one ;
(xx) (S)-3-(1-hydroxypropan-2-yl)-6,8-di(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one;
(xxi) 6-(4-chlorophenyl)-3-(2-hydroxy-2-methylpropyl)-8-(1-methyl-1H-pyrazol-4-yl)pyrido[3,4-d]pyrimidine-4 (3H)-on;
(xxii) (S)-3-(1-hydroxypropan-2-yl)-8-(pyridin-3-yl)-6-(4-(trifluoromethoxy)phenyl)pyrido[3,4-d] pyrimidin-4(3H)-one;
(xxiii) (S)-3-(1-hydroxypropan-2-yl)-8-(pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrido[3,4-d] pyrimidin-4(3H)-one;
(xxiv) (S)-6-(4-chlorophenyl)-3-(1-hydroxypropan-2-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidine-4(3H )-on;
(xxv) (S)-3-(1-hydroxypropan-2-yl)-8-(1-methyl-1H-pyrazol-4-yl)-6-(4-(trifluoromethoxy)phenyl)pyrido [ 3,4-d]pyrimidin-4(3H)-one;
(xxvi) (S)-3-(1-hydroxypropan-2-yl)-8-(1-methyl-1H-pyrazol-4-yl)-6-phenylpyrido[3,4-d]pyrimidine-4 ( 3H)—on;
(xxvii) (S)-6-(4-chlorophenyl)-3-(1-hydroxypropan-2-yl)-8-(1-methyl-1H-pyrazol-4-yl)pyrido [3,4-d ] pyrimidin-4(3H)-one;
(xxviii) 3-methyl-8-(pyridin-3-yl)-6-(4-(trifluoromethoxy)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one;
(xxix) Rac-6-(4-chlorophenyl)-3-((trans)-4-hydroxytetrahydrofuran-3-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidine-4 (3H)-on;
(xxx) (S)-6-(4-chlorophenyl)-3-(3-hydroxy-3-methylbutan-2-yl)-8-(1-methyl-1H-pyrazol-4-yl)pyrido [3, 4-d]pyrimidin-4(3H)-one;
(xxxi) (R)-6-(4-chlorophenyl)-3-(3-hydroxy-3-methylbutan-2-yl)-8-(1-methyl-1H-pyrazol-4-yl)pyrido [3, 4-d]pyrimidin-4(3H)-one;
(xxxii) rac-6-(4-chlorophenyl)-3-((cis)-4-hydroxytetrahydrofuran-3-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidine-4 (3H)-on;
(xxxiii) (R)-6-(4-chlorophenyl)-3-(3-hydroxy-3-methylbutan-2-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidine- 4(3H)-on;
(xxxiv) (S)-3-(3-hydroxy-3-methylbutan-2-yl)-6,8-di(pyridin-3-yl)pyrido[3,4-d]pyrimidine-4(3H)- on;
(xxxv) (S)-6,8-bis(3,5-difluorophenyl)-3-(1-hydroxy-3-methylbutan-2-yl)pyrido[3,4-d]pyrimidine-4(3H) -on;
(xxxvi) (S)-6-(4-chlorophenyl)-3-(3-hydroxy-3-methylbutan-2-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidine- 4(3H)-on;
(xxxvii) (S)-8-(3,5-difluorophenyl)-3-(1-hydroxy-3-methylbutan-2-yl)-6-(p-tolyl)pyrido[3,4-d]pyrimidine -4(3H)-one;
(xxxviii) 6-(4-chlorophenyl)-8-(3-fluorophenyl)-3-(2-hydroxy-2-methylpropyl)pyrido[3,4-d]pyrimidin-4(3H)-one;
(xxxix) (R)-6-(4-chlorophenyl)-8-(3-fluorophenyl)-3-(3-hydroxy-3-methylbutan-2-yl)pyrido[3,4-d]pyrimidine-4 (3H)-on;
(xl) (S)-3-(1-(benzyloxy)propan-2-yl)-8-(3-fluorophenyl)-6-(p-tolyl)pyrido[3,4-d]pyrimidine-4 (3H)-on;
(xli) (R)-6-(4-chlorophenyl)-8-(3-fluorophenyl)-3-(3,3,3-trifluoro-2-hydroxypropyl)pyrido[3,4-d]pyrimidine -4(3H)-one;
(xlii) (S)-6-(4-chlorophenyl)-8-(3-fluorophenyl)-3-(3,3,3-trifluoro-2-hydroxypropyl)pyrido[3,4-d]pyrimidine -4(3H)-one;
(xliii) (S)-3-(1-hydroxypropan-2-yl)-6-morpholin-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one;
(xliv) (S)-3-(1-hydroxypropan-2-yl)-8-(1H-imidazol-1-yl)-6-(4-(trifluoromethoxy)phenyl)pyrido[3,4- d] pyrimidin-4(3H)-one;
(xlv) (S)-3-(1-methoxypropan-2-yl)-8-(pyridin-3-yl)-6-(p-tolyl)pyrido[3,4-d]pyrimidine-4 (3H )-on;
(xlvi) (S)-3-(1-hydroxypropan-2-yl)-8-(pyridin-3-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido [3, 4-d]pyrimidin-4(3H)-one;
(xlvii) (S)-8-(3-fluorophenyl)-3-(1-hydroxypropan-2-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4 -d]pyrimidin-4(3H)-one;
(xlviii) (S)-8-(3-fluorophenyl)-3-(1-hydroxypropan-2-yl)-6-(p-tolyl)pyrido[3,4-d]pyrimidine-4(3H) -on;
(xlix) (S)-8-(3-fluorophenyl)-3-(1-hydroxypropan-2-yl)-6-(4-(trifluoromethoxy)phenyl)pyrido[3,4-d]pyrimidine -4(3H)-one;
(l) (S)-3-(1-hydroxypropan-2-yl)-8-(pyridin-3-yl)-6-(6-(trifluoromethoxy)pyridin-3-yl)pyrido [3, 4-d]pyrimidin-4(3H)-one (li)(S)-3-(2-hydroxy-2-methylpropyl)-8-(1H-pyrazol-4-yl)-6-(6-( trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (lii)methyl (S)-5-(3-(1-hydroxypropan-2-yl)- 4-oxo-8-(pyridin-3-yl)-3,4-dihydropyrido[3,4-d]pyrimidin-6-yl)picolinate (liii) (S)-3-(1-hydroxypropane-2- yl)-6-(isothiazol-4-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (liv) 3-(2-hydroxy-2 -methylpropyl)-8-(isothiazol-4-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (lv ) (S)-3-(1-hydroxypropan-2-yl)-8-(isothiazol-4-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido [3,4 -d]pyrimidin-4(3H)-one (lvi)(S)-3-(1-hydroxypropan-2-yl)-6,8-di(isothiazol-4-yl)pyrido[3,4- d]pyrimidin-4(3H)-one (lvii)(S)-8-(pyridin-3-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)-6-(6- (trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (lviii) (S)-6-(4-chlorophenyl)-3-(1-hydroxypropane- 2-yl)-8-(isothiazol-4-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (lix) 3-(2-hydroxy-2-methylpropyl)-6,8 -di(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (lx) 3-(2-hydroxy-2-methylpropyl)-8-(1-methyl-1H- pyrazol-4-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (lxi) 6-(4-chloro- 2-methylphenyl)-3-(2-hydroxy-2-methylpropyl)-8-(1-methyl-1H-pyrazol-4-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (lxii) (S)-3-(1-hydroxypropan-2-yl)-8-(1H-pyrazol-4-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido [ 3,4-d]pyrimidin-4(3H)-one (lxiii) (S)-3-(1-hydroxypropan-2-yl)-8-(2-methylpyridin-3-yl)-6-( 6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (lxiv) (S)-3-(1-hydroxypropan-2-yl)-8 -(4-methylpyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (lxv) (S) -3-(1-hydroxypropan-2-yl)-6-(4-methylthiazol-5-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidine-4(3H) -one (lxvi) (S)-6-(2-cyclopropylthiazol-5-yl)-3-(1-hydroxypropan-2-yl)-8-(pyridin-3-yl)pyrido[3,4 -d]pyrimidin-4(3H)-one (lxvii) (S)-3-(1-hydroxypropan-2-yl)-6-(2-isopropylthiazol-5-yl)-8-(pyridin-3 -yl)pyrido[3,4-d]pyrimidin-4(3H)-one (lxviii) (S)-3-(1-hydroxypropan-2-yl)-8-(1-methyl-1H-pyrazole- 4-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (lxix)(S)-3-(1-hydroxy propan-2-yl)-6,8-bis(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (lxx)6-(4- Chlorophenyl)-3-((3S,4S)-4-hydroxytetrahydrofuran-3-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (lxxi) 6-(4-chlorophenyl)-3-((3R,4R)-4-hydroxytetrahydrofuran-3-yl)-8-(pyridin-3-yl) pyrido[3,4-d]pyrimidin-4(3H)-one (lxxii) 3-(2-hydroxyethyl)-8-(pyridin-3-yl)-6-(4-(trifluoromethoxy)phenyl) pyrido[3,4-d]pyrimidin-4(3H)-one (lxxiii)(S)-6-(4-chlorophenyl)-3-(1-hydroxypropan-2-yl)-8-(1-methyl -6-oxo-1,6-dihydropyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (lxxiv)(S)-6-(6-cyclopropylpyridin-3-yl )-3-(1-hydroxypropan-2-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (lxxv)(S)-3-( 1-hydroxypropan-2-yl)-6-(4-methyl-6-(trifluoromethyl)pyridin-3-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidine- 4(3H)-one (lxxvi)(S)-3-(1-hydroxypropan-2-yl)-8-(1-methyl-1H-pyrazol-4-yl)-6-(pyridin-3-yl ) pyrido[3,4-d]pyrimidin-4(3H)-one (lxxvii) (S)-6-(cyclohex-1-en-1-yl)-3-(1-hydroxypropan-2-yl) -8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (lxxviii)(S)-6,8-bis(5-fluoropyridin-3-yl)-3 -(1-hydroxypropan-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (lxxix)3-((3R,4S)-4-hydroxytetrahydrofuran-3-yl)-8 -(pyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (lxxx)3-(2-hydroxy -2-methylpropyl)-8-(pyridin-3-yl)-6-(2-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one ( lxxxi) 6-(6-cyclopropylpyridin-3-yl)-3-(2-hydroxy-2-methylpropyl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidine-4 ( 3H)-one (lxxxii) 6-(6-cyclopropylpyridin-3-yl)-3-(2-hydroxy-2-methyl propyl)-8-(1-methyl-1H-pyrazol-4-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (lxxxiii)(S)-6-(6-cyclopropylpyridine- 3-yl)-3-(1-hydroxypropan-2-yl)-8-(1-methyl-1H-pyrazol-4-yl)pyrido[3,4-d]pyrimidin-4(3H)-one ( lxxxiv) (S)-3-(1-hydroxypropan-2-yl)-8-(pyridin-3-yl)-6-(thiazol-5-yl)pyrido[3,4-d]pyrimidine-4 ( 3H)-one (lxxxv)(S)-3-(1-hydroxypropan-2-yl)-8-(pyridin-3-yl)-6-(2-(trifluoromethyl)thiazol-5-yl) pyrido[3,4-d]pyrimidin-4(3H)-one (lxxxvi)(S)-3-(1-hydroxypropan-2-yl)-8-(pyridin-3-yl)-6-(2 -(trifluoromethyl)pyrimidin-5-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (lxxxvii) 3-(2-hydroxy-2-methylpropyl)-8-(pyridine-3 -yl)-6-(2-(trifluoromethyl)thiazol-5-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (lxxxviii)3-((3S,4S)-4- Hydroxytetrahydrofuran-3-yl)-8-(1-methyl-1H-pyrazol-4-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidine- 4(3H)-one (lxxxix)(S)-3-(1-hydroxypropan-2-yl)-6-(2-methylthiazol-5-yl)-8-(pyridin-3-yl)pyrido [ 3,4-d]pyrimidin-4(3H)-one (xc)(S)-6-(4-chlorophenyl)-8-(3-fluorophenyl)-3-(1-hydroxy-3-methylbutane-2 -yl)pyrido[3,4-d]pyrimidin-4(3H)-one (xci)(S)-3-(1-hydroxypropan-2-yl)-6-(piperidin-1-yl)-8 -(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (xcii) 3-(2-hydroxy-2-methylpropyl)-8-(isothiazol-4-yl) -6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidine-4(3 H)-one (xciii) (S)-3-(1-hydroxypropan-2-yl)-8-(isothiazol-4-yl)-6-(5-(trifluoromethyl)pyridin-2-yl ) pyrido[3,4-d]pyrimidin-4(3H)-one (xciv) 3-(2-hydroxy-2-methylpropyl)-8-(1-methyl-1H-pyrazol-4-yl)-6 -(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (xcv)(S)-8-(pyridin-3-yl)-3- (3,3,3-trifluoro-2-hydroxypropyl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (xcvi ) (3-(2-hydroxy-2-methylpropyl)-8-(pyridin-3-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidine -4(3H)-one (xcvii) 3-(1,1-dioxidotetrahydrothiophen-3-yl)-8-(pyridin-3-yl)-6-(6-(trifluoromethyl)pyridine-3 -yl)pyrido[3,4-d]pyrimidin-4(3H)-one (xcviii) (R)-3-(1,1-dioxidotetrahydrothiophen-3-yl)-8-(pyridin-3- yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (xcix) (R)-3-(2-hydroxypropyl) -8-(1-methyl-1H-pyrazol-4-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one ( c) (S)-3-(2-hydroxypropyl)-8-(1-methyl-1H-pyrazol-4-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido [3 ,4-d]pyrimidin-4(3H)-one (ci)(R)-8-(1-methyl-1H-pyrazol-4-yl)-3-(3,3,3-trifluoro-2- Hydroxypropyl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cii)(S)-8-(1-methyl- 1H-pyrazol-4-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)-6-(6-(trifluoromethyl)pyridine-3 -yl)pyrido[3,4-d]pyrimidin-4(3H)-one (ciii) (R)-3-(2-hydroxypropyl)-8-(pyridin-3-yl)-6-(6- (trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (civ) (R)-8-(1-methyl-1H-pyrazol-4-yl)- 3-(3,3,3-trifluoro-2-hydroxypropyl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cv) 3-((3S,4R)-4-hydroxytetrahydrofuran-3-yl)-8-(1-methyl-1H-pyrazol-4-yl)-6-(6-(trifluoromethyl)pyridine- 3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cvi) 3-((3R,4S)-4-hydroxytetrahydrofuran-3-yl)-8-(1-methyl-1H -pyrazol-4-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cvii)6-(4-chlorophenyl) -3-((3S,4R)-4-hydroxytetrahydrofuran-3-yl)-8-(1-methyl-1H-pyrazol-4-yl)pyrido[3,4-d]pyrimidine-4(3H)- On (cviii) 3-((3S,4R)-4-hydroxytetrahydrofuran-3-yl)-8-(pyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido [3,4-d]pyrimidin-4(3H)-one (cix)(S)-6-(6-cyclopropylpyridin-3-yl)-8-(pyridin-3-yl)-3-(3 ,3,3-trifluoro-2-hydroxypropyl)pyrido[3,4-d]pyrimidin-4(3H)-one (cx)(R)-6-(6-cyclopropylpyridin-3-yl)- 8-(pyridin-3-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxi)(R)- 8-(pyridin-3-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido [3,4- d]pyrimidin-4(3H)-one (cxii) (R)-8-(pyridin-3-yl)-3-(3,3,3-trifluoro-2- Hydroxypropyl)-6-(4-(trifluoromethoxy)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxiii)(S)-8-(pyridin-3-yl)-3 -(3,3,3-trifluoro-2-hydroxypropyl)-6-(4-(trifluoromethoxy)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxiv)6- (4-chlorophenyl)-3-((3S,4R)-4-hydroxytetrahydrofuran-3-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxv) 3-((3S,4S)-4-hydroxytetrahydrofuran-3-yl)-8-(pyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido [ 3,4-d]pyrimidin-4(3H)-one (cxvi)methyl (S)-2-(4-oxo-8-(pyridin-3-yl)-6-(6-(trifluoromethyl)pyridine -3-yl)pyrido[3,4-d]pyrimidin-3(4H)-yl)propanoate (cxvii) 6-(4-chlorophenyl)-3-(4-hydroxy-1-methylpyrrolidin-3-yl) -8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxviii)6-(4-chlorophenyl)-3-((3R,4R)-4-hydroxypyrrolidine -3-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxix)(R)-6-(6-cyclopropylpyridin-3-yl )-8-(1-methyl-1H-pyrazol-4-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)pyrido[3,4-d]pyrimidine-4(3H)- On (cxx)(S)-6-(6-cyclopropylpyridin-3-yl)-8-(1-methyl-1H-pyrazol-4-yl)-3-(3,3,3-trifluoro- 2-hydroxypropyl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxxi) 3-((3S,4R)-4-hydroxytetrahydrofuran-3-yl)-8-(1-methyl- 1H-pyrazol-4-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxxii)3-((3R, 4S)-4-hydroxytetrahydrofuran-3-yl)-8-(1-methyl -1H-pyrazol-4-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxxiii)3-((3S , 4R)-4-hydroxytetrahydrofuran-3-yl)-8-(pyridin-3-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidine- 4(3H)-one (cxxiv) 3-((3R,4S)-4-hydroxytetrahydrofuran-3-yl)-8-(pyridin-3-yl)-6-(5-(trifluoromethyl)pyridine- 2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxxv) (R)-3-(2-hydroxypropyl)-8-(1-methyl-1H-pyrazol-4-yl )-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxxvi)(S)-3-(2-hydroxypropyl)- 8-(1-methyl-1H-pyrazol-4-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxxvii ) (S)-3-(2-hydroxypropyl)-8-(pyridin-3-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidine- 4(3H)-one (cxxviii) (R)-3-(2-hydroxypropyl)-8-(pyridin-3-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido [ 3,4-d]pyrimidin-4(3H)-one (cxxix)3-((3S,4S)-4-hydroxytetrahydrofuran-3-yl)-8-(pyridin-3-yl)-6-(5 -(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxxx)(S)-3-(2-hydroxypropyl)-8-(pyridine-3 -yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxxxi)(S)-8-(1-methyl- 1H-pyrazol-4-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido [3,4-d ] pyrimidin-4(3H)-one (cxxxii)(S)-3-(1-hydroxypropane-2 -yl)-8-(1-methyl-1H-pyrazol-4-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidine-4(3H) -one (cxxxiii) 3-((3S,4S)-4-hydroxytetrahydrofuran-3-yl)-8-(1-methyl-1H-pyrazol-4-yl)-6-(5-(trifluoromethyl) pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxxxiv) 6-(4-chlorophenyl)-3-((3R,4S)-4-hydroxytetrahydrofuran-3-yl )-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxxxv)6-(4-chlorophenyl)-3-((3R,4S)-4-hydroxy Tetrahydrofuran-3-yl)-8-(1-methyl-1H-pyrazol-4-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxxxvi) (R)-8-(pyridine- 3-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidine-4 (3H)-one (cxxxvii)(S)-2-(4-oxo-8-(pyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4 -d]pyrimidin-3(4H)-yl)propanoic acid (cxxxviii) (S)-N-methyl-2-(4-oxo-8-(pyridin-3-yl)-6-(6-(trifluoro methyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-3(4H)-yl)propanamide (cxxxix) (S)-N,N-dimethyl-2-(4-oxo-8-( Pyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-3(4H)-yl)propenamide (cxl) 3-(2- Hydroxy-2-methylpropyl)-8-(1H-pyrazol-4-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidine-4(3H) -one (cxli) 3-(2-hydroxy-2-methylpropyl)-8-(1H-imidazol-1-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido [3, 4-d]pyrimidin-4(3H)-one (cxlii) 3-(2-hydroxy -2-methylpropyl)-8-(1H-imidazol-1-yl)-6-(6-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidine-4(3H)- On (cxliii) (S)-3-(1-hydroxypropan-2-yl)-8-(1H-imidazol-1-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido [3,4-d]pyrimidin-4(3H)-one (cxliv) (S)-3-(1-hydroxypropan-2-yl)-8-(1H-imidazol-1-yl)-6-( 6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxlv)(S)-3-(1-hydroxypropan-2-yl)-8 -(1H-1,2,4-triazol-1-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one ( cxlvi) (S)-3-(1-hydroxypropan-2-yl)-8-(1H-pyrazol-1-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido [3 , 4-d]pyrimidin-4(3H)-one (cxlvii) (S)-3-(1-hydroxypropan-2-yl)-8-(1-methyl-1H-pyrazol-4-yl)-6 -(2-(trifluoromethyl)thiazol-5-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxlviii)(S)-8-(diethylamino)-3-(1-hydroxy Propan-2-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxlix)(S)-3-(1 -hydroxypropan-2-yl)-8-(piperidin-1-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidine-4(3H)- On (cl) (S)-3-(1-hydroxypropan-2-yl)-8-(pyrrolidin-1-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido [3 ,4-d]pyrimidin-4(3H)-one (cli)(S)-6-(4-chlorophenyl)-3-(1-hydroxypropan-2-yl)-8-(piperidin-1-yl) pyrido[3,4-d]pyrimidin-4(3H)-one (clii)(S)-3-(1-hydroxypropan-2-yl)-8- (pyridin-2-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cliiii)(S)-6-cyclohexyl -3-(1-hydroxypropan-2-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cliv)(S)-3-(1 -hydroxypropan-2-yl)-6-(pyridin-2-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (clv) (S) -3-(1-hydroxypropan-2-yl)-6-(2-methylthiazol-4-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidine-4(3H) -one (clvi) (S)-3-(1-hydroxypropan-2-yl)-6-(1-methyl-1H-1,2,3-triazol-5-yl)-8-(pyridin-3 -yl)pyrido[3,4-d]pyrimidin-4(3H)-one (clvii)(R)-6-(4-chlorophenyl)-8-(pyridin-3-yl)-3-(3,3 ,3-trifluoro-2-hydroxypropyl)pyrido[3,4-d]pyrimidin-4(3H)-one;
(clviii) (S)-6-(4-chlorophenyl)-8-(pyridin-3-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)pyrido[3,4-d] pyrimidin-4(3H)-one;
(clix) (S)-3-(1-hydroxypropan-2-yl)-8-(1-methyl-1,2,5,6-tetrahydropyridin-3-yl)-6-(6-(tri fluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (clx)6-(4-chlorophenyl)-3-((3S,4S)-4-hydroxytetrahydrofuran- 3-yl)-8-(1-methyl-1H-pyrazol-4-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (clxi)(S)-3-(1-hydroxypropane -2-yl)-6-(2-methylpyrimidin-5-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (clxii)3-( 2-hydroxy-2-methylpropyl)-8-(1-(trifluoromethyl)-1H-pyrazol-4-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido [3, 4-d]pyrimidin-4(3H)-one (clxiii) (S)-3-(1-hydroxypropan-2-yl)-8-(1-methyl-1H-pyrazol-4-yl)-6- (2-(trifluoromethyl)pyrimidin-5-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (clxiv) 3-(2-hydroxy-2-methylpropyl)-8-(pyridine -3-yl)-6-(2-(trifluoromethyl)pyrimidin-5-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (clxv)(S)-5-(3- (1-hydroxypropan-2-yl)-4-oxo-8-(pyridin-3-yl)-3,4-dihydropyrido[3,4-d]pyrimidin-6-yl)picolinic acid (clxvi) (S )-3-(1-hydroxypropan-2-yl)-6-(6-methylpyridin-3-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidine-4 (3H )-one (clxvii) 3-(2-hydroxy-2-methylpropyl)-8-(1-methyl-1H-pyrazol-4-yl)-6-(2-(trifluoromethyl)pyrimidin-5-yl ) pyrido[3,4-d]pyrimidin-4(3H)-one (clxviii) 3,8-di(pyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido [3,4-d]pyrimidin-4(3H)-one (clxix)8-(pyridin-3-yl)-6-(6-( trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (clxx)3-((3R,4R)-4-hydroxytetrahydrofuran-3-yl)-8- (pyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (clxxi)3-((3R,4R )-4-hydroxytetrahydrofuran-3-yl)-8-(1-methyl-1H-pyrazol-4-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4- d]pyrimidin-4(3H)-one (clxxii) 6-(4-chlorophenyl)-3-((3R,4R)-4-hydroxytetrahydrofuran-3-yl)-8-(1-methyl-1H-pyrazole -4-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (clxxiii) 3-cyclopentyl-8-(pyridin-3-yl)-6-(6-(trifluoromethyl)pyridine- 3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (clxxiv) 3-phenyl-8-(pyridin-3-yl)-6-(6-(trifluoromethyl)pyridine-3 -yl)pyrido[3,4-d]pyrimidin-4(3H)-one (clxxv) 3-((3R,4R)-4-hydroxytetrahydrofuran-3-yl)-8-(pyridin-3-yl) -6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (clxxvi)3-((3R,4R)-4-hydroxytetrahydrofuran- 3-yl)-8-(1-methyl-1H-pyrazol-4-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidine-4(3H )-one (clxxvii) (S)-3-(1-hydroxypropan-2-yl)-8-(1-methyl-1H-pyrazol-4-yl)-6-(5-(trifluoromethyl)pyridine -2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (clxxviii)(S)-N-((3R,4S)-4-hydroxytetrahydrofuran-3-yl)-2-( 4-oxo-8-(pyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-3(4H)-yl)propanamide ( clxxix)3-(2-hi droxy-2-methylpropyl)-8-(1H-pyrazol-4-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidine-4(3H) -one (clxxx)(S)-6-(4-chlorophenyl)-3-(1-hydroxypropan-2-yl)-8-(1H-pyrazol-1-yl)pyrido[3,4-d]pyrimidine -4(3H)-one (clxxxi)(S)-3-(1-hydroxypropan-2-yl)-8-(1H-pyrazol-1-yl)-6-(5-(trifluoromethyl)pyridine -2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (clxxxii)3-((3S,4R)-4-hydroxytetrahydrofuran-3-yl)-8-(pyridin-3- yl)-6-(2-(trifluoromethyl)thiazol-5-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (clxxxiii)3-(2-hydroxy-2-methylpropyl) -8-(1-methyl-1H-pyrazol-4-yl)-6-(2-(trifluoromethyl)thiazol-5-yl)pyrido[3,4-d]pyrimidin-4(3H)-one ( clxxxiv) 3-((3S,4R)-4-hydroxytetrahydrofuran-3-yl)-8-(1-methyl-1H-pyrazol-4-yl)-6-(2-(trifluoromethyl)thiazole-5 -yl)pyrido[3,4-d]pyrimidin-4(3H)-one (clxxxv)3-((3R,4S)-4-hydroxytetrahydrofuran-3-yl)-8-(1-methyl-1H- pyrazol-4-yl)-6-(2-(trifluoromethyl)thiazol-5-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (clxxxvi) 3-((3R,4S) -4-hydroxytetrahydrofuran-3-yl)-8-(pyridin-3-yl)-6-(2-(trifluoromethyl)thiazol-5-yl)pyrido[3,4-d]pyrimidine-4(3H )-one (clxxxvii) (S)-3-(1-hydroxypropan-2-yl)-8-morpholino-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido [3,4-d ] pyrimidin-4(3H)-one (clxxxviii) 3-(2-hydroxy-2-methylpropyl)-8-(piperidin-1-yl)-6-(6-(trifluoromethyl)pyridin-3-yl ) pyrido [3,4-d]pyrimidin-4(3H)-one (clxxxix)(S)-3-(1-hydroxypropan-2-yl)-6-(5-methylpyridin-2-yl)-8- (pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxc)(S)-3-(1-hydroxypropan-2-yl)-6-(5-methylpyrimidine -2-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxci)(S)-8-(cyclohex-1-en-1-yl )-3-(1-hydroxypropan-2-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxcii) (S)-8-cyclohexyl-3-(1-hydroxypropan-2-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidine-4 (3H )-one (cxciii) (S)-3-(1-hydroxypropan-2-yl)-N,N-dimethyl-4-oxo-8-(pyridin-3-yl)-3,4-dihydropyrido [3 ,4-d]pyrimidine-6-carboxamide (cxciv) (S)-3-(1-hydroxypropan-2-yl)-8-(1H-pyrazol-4-yl)-6-(5-(trifluoro Methyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxcv) (S)-3-(1-hydroxypropan-2-yl)-6-(2-methoxy Ethyl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxcvi)(S)-3-(1-hydroxypropan-2-yl)-8- (2-Methoxyethyl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one. A pharmaceutical composition comprising at least one entity selected from the compounds according to any one of claims 1 to 29 and pharmaceutically acceptable salts thereof and at least one pharmaceutically acceptable excipient . A method of treating a disease or condition mediated by AhR signaling in a subject in need of treatment of a disease or condition mediated by AhR signaling, comprising administering to said subject a therapeutically effective amount of 31. A method comprising administering at least one entity selected from a compound according to any one of claims and pharmaceutically acceptable salts thereof or at least one pharmaceutical composition according to claim 30. A method of treating a disease or condition associated with aberrant AhR signaling in a subject in need of treatment of a disease or condition associated with aberrant AhR signaling, comprising administering to said subject a therapeutically effective amount of claim 1- 31. A method comprising administering at least one entity selected from a compound according to any one of claims 29 and pharmaceutically acceptable salts thereof or at least one pharmaceutical composition according to claim 30. 33. The method of claim 31 or 32, wherein said disease is selected from cancer. 33. The method of claim 31 or 32, wherein said disease is selected from liquid tumors and solid tumors. the disease is breast cancer, respiratory tract cancer, brain cancer, genital cancer, gastrointestinal cancer, urinary tract cancer, eye cancer, liver cancer, skin cancer, head and neck cancer, thyroid cancer, parathyroid cancer, and any of the above 35. The method of any one of claims 31-34, wherein the method is selected from transitions of A method according to any one of claims 31 to 35, wherein said disease is selected from breast cancer, pancreatic cancer, prostate cancer and colon cancer. The method of any one of claims 31-34, wherein the disease is selected from lymphoma, sarcoma, melanoma, glioblastoma, and leukemia. A method of inhibiting cancer cell growth mediated by AHR signaling in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of any of claims 1-29. 31. A method comprising administering at least one entity selected from a compound according to any one of claims and pharmaceutically acceptable salts thereof or at least one pharmaceutical composition according to claim 30. A method of inhibiting AhR signaling-mediated tumor cell invasion or metastasis in a subject in need of inhibition of AhR signaling-mediated tumor cell invasion or metastasis, comprising administering to said subject a therapeutically effective amount of administering at least one entity selected from compounds according to any one of claims 1 to 29 and pharmaceutically acceptable salts thereof or at least one pharmaceutical composition according to claim 30 Method. A method of treating cancer in a subject in need thereof, comprising: administering to said subject a therapeutically effective amount of i) a compound of any one of claims 1-29 and a pharmaceutically acceptable dose thereof; or at least one pharmaceutical composition according to claim 30, and ii) a therapeutically effective amount of at least one additional therapy. 41. The method of claim 40, wherein said at least one additional therapy comprises at least 2, at least 3, at least 4, or at least 5 additional therapies. administration of said at least one entity selected from compounds according to any one of claims 1 to 29 and pharmaceutically acceptable salts thereof or at least one pharmaceutical composition according to claim 30 41. The method of claim 40, started prior to administration of said at least one additional therapy. Said at least one entity selected from compounds according to any one of claims 1 to 29 and pharmaceutically acceptable salts thereof or at least one pharmaceutical composition according to claim 30, said 41. The method of claim 40, administered after administration of at least one additional therapy. Said at least one entity selected from compounds according to any one of claims 1 to 29 and pharmaceutically acceptable salts thereof or at least one pharmaceutical composition according to claim 30, said 41. The method of claim 40, administered concurrently with administration of at least one additional therapy. 45. The method of any one of claims 40-44, wherein said at least one additional therapy is selected from checkpoint inhibitors. 46. The method of claim 45, wherein said subject is intolerant, refractory and/or poorly responsive when said at least one additional therapy is administered alone. The at least one additional therapy is selected from checkpoint inhibitors targeting CTLA-4, PD-1, PD-L1, LAG-3, TIM-3, TIGIT, and/or VISTA. 46. The method according to 46. 47. The method of claim 46, wherein said at least one additional therapy is selected from checkpoint inhibitors targeting CTLA-4, PD-1 and/or PD-L1. 47. The method of claim 46, wherein said at least one additional therapy is selected from cytotoxic T lymphocyte-associated antigen 4 pathway inhibitors. 50. The method of claim 49, wherein said cytotoxic T lymphocyte-associated antigen 4 pathway inhibitor is selected from anti-CTLA-4 antibodies. 51. The method of claim 50, wherein said anti-CTLA-4 antibody is ipilimumab. 47. The method of claim 46, wherein said at least one additional therapy is selected from programmed death-1 pathway inhibitors. 53. The method of claim 52, wherein said programmed death-1 pathway inhibitor is selected from anti-PD-1 antibodies. 53. The method of claim 52, wherein said anti-PD-1 antibody is nivolumab. 53. The method of claim 52, wherein said anti-PD-1 antibody is pembrolizumab. 53. The method of claim 52, wherein said anti-PD-1 antibody is semiplimab. 53. The method of claim 52, wherein said anti-PD-1 antibody is camrelizumab. 53. The method of claim 52, wherein said anti-PD-1 antibody is Scintilimab. 53. The method of claim 52, wherein said anti-PD-1 antibody is spartalizumab. 53. The method of claim 52, wherein said anti-PD-1 antibody is tislelizumab. 53. The method of claim 52, wherein said anti-PD-1 antibody is BCD-100. 53. The method of claim 52, wherein said anti-PD-1 antibody is JS001. 53. The method of claim 52, wherein said programmed death-1 pathway inhibitor is selected from anti-PD-L1 antibodies. 64. The method of claim 63, wherein said anti-PD-L1 antibody is atezolizumab. 64. The method of claim 63, wherein said anti-PD-L1 antibody is avelumab. 64. The method of claim 63, wherein said anti-PD-L1 antibody is durvalumab. 64. The method of claim 63, wherein said anti-PD-L1 antibody is KN035. 47. The method of claim 46, wherein said at least one additional therapy is selected from lymphocyte activation gene-3 (LAG-3) inhibitors. 69. The method of claim 68, wherein said LAG-3 inhibitor is selected from anti-LAG-3 antibodies. 47. The method of claim 46, wherein said at least one additional therapy is selected from T cell immunoglobulins and mucin domain containing-3 (TIM-3) inhibitors. 71. The method of claim 70, wherein said TIM-3 inhibitor is selected from anti-TIM-3 antibodies. 47. The method of claim 46, wherein said at least one additional therapy is selected from T cell immunoglobulins and ITIM domain (TIGIT) inhibitors. 73. The method of claim 72, wherein said TIGIT inhibitor is selected from TIGIT antibodies. 47. The method of claim 46, wherein said at least one additional therapy is selected from V-domain Ig suppressor of T cell activation (VISTA) inhibitors. 75. The method of claim 74, wherein said VISTA inhibitor is selected from anti-VISTA antibodies. squamous cell carcinoma of the head and neck; renal cell carcinoma; adenocarcinoma of the stomach; nasopharyngeal neoplasm; Negative breast cancer (TNBC); esophageal neoplasms; multiple myeloma; gastric and esophagogastric junction cancer; melanoma; esophagogastric junction cancer; metastatic melanoma; metastatic noncutaneous melanoma; urothelial carcinoma; diffuse large B-cell lymphoma; renal cell carcinoma; cancer; peritoneal neoplasm; extensive small cell lung cancer; bladder cancer; transitional cell carcinoma; prostatic neoplasm; Lung cancer; advanced solid malignancies; SCCHN; hypopharyngeal squamous cell carcinoma; laryngeal squamous cell carcinoma; unresectable or metastatic melanoma; 76. The method of any one of claims 40-75, selected from prostate cancer, solid organ cancer; gastric cancer; colon cancer; and liver cancer.

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